Rozprawy doktorskie: „INTEGRATIVE TRANSCRIPTOME”

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Padvitski, Tsimafei. "Integrative analysis of age-related changes in the transcriptome of Caenorhabditis elegans". Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-11825.

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Ageing is difficult to study because of the complexity and multi-factorial nature of traits that result from a combination of environmental, genetic, epigenetic and stochastic factors, each contributing to the overall phenotype. In light of this challenge, transcriptomic studies of aging organisms are of particular interest, since transcription is an intermediate step that links genotype and phenotype. In recent years microarrays have been widely used for elucidation of changes that occur with age in the transcriptome in Caenorhabditis elegans. However, different microarray studies of C. elegans report sets of differentially expressed genes of varying consistence, with different functional annotations. Failures to find a consistent set of transcriptomic alterations may reflect the absence of a specific genetic program that would guide age-related changes but may also, to some extent, be a consequence of a small sample sizes and a lack of study power in transcriptomic researches. To tackle this issue we analyzed RNA sequences of samples from a time-series experiment of normal aging of C. elegans, performing the first, to our knowledge, NGS-based study of such kind. As a result, evidences were collected that promote a union of two competing theories: the theory of DNA damage accumulation and the theory of programmed aging. Next, we applied two alternative methods, namely the Short Time-series Expression Mining and the Network Smoothing algorithm, in order to obtain and analyze sets of genes that represent distinct modules of age-related changes in the transcriptome. Besides characterization of age-related changes, we were also interested in assessment and validation of the Network Smoothing algorithm. Generally, results of clustering of smoothed scores are consistent with results of short time-series clustering, allowing robust elucidation of functions that are perturbed during aging. At the last phase of the project we questioned if observed changes in the transcriptome can be controlled by specific transcription factors. Thus we used Chip-seq data to predict plausible transcription factor regulators of gene sets obtained using time series clustering and Network smoothing. On the one hand, all predicted transcription factors had documented relevance to aging. On the other hand, we did not achieve gene set specific prediction of transcription factors. In fact, genes with the opposite dynamics were predicted to respond to the same transcription factors. To summarize, we characterized in details age-related changes in the transcriptome of C. elegans, validated the performance of the Network Smoothing algorithm and showed that integration of gene expression with Chip-seq data allows to predict transcription factors that are capable to modulate the lifespan of C. elegans.

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Wilson, Rebecca. "Investigating the Interaction of Monoamines and Diel Rhythmicity on Anti-Predator Behavior in an Orb-Weaving Spider, Larinioides cornutus (Araneae: Araneae)". Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/etd/3441.

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Circadian rhythms are ubiquitous among organisms, influencing a wide array of physiological processes and behaviors including aggression. While many neurophysiological mechanisms are involved in the regulation of aggressive behaviors, relatively few studies have investigated the underlying components involved in the interplay between circadian rhythms and aggression. Spiders are an ideal model system for studying circadian regulation of aggression as they are ecologically both predators and prey. Recent studies have revealed a nocturnal orb- weaving spider Larinioides cornutus exhibits a diel and circadian rhythm in anti-predator behavior (i.e. boldness) that can be manipulated by administration of octopamine (OA) and serotonin (5- HT). Dosing of OA increases boldness of an individual while 5-HT decreases boldness levels. Thus, it appears the serotonergic and octopaminergic system are playing a key role in the daily fluctuations of boldness. This study took a holistic approach to investigate OA and 5-HT levels of head tissue and hemolymph (i.e. blood) as well as the genes involved in synthesis, signaling, and degradation of these monoamines throughout the day (0100, 0700, 1300, and 1900 hours) using HPLC-ED and RNA-sequencing. Although endogenous and circulating levels of OA did not significantly fluctuate, putative transcripts involved in synthesis and signaling did increase in relative expression levels at dusk when L. cornutus begins to actively forage for prey. Endogenous and circulating levels of 5-HT also did not significantly change at the four different time points, but clear patterns of upregulation of 5-HT synthesis enzymes as well as some receptor transcripts were upregulated during the day when L. cornutus would be mostly inactive in its retreat. Lastly, monoamine oxidase, a major catabolic enzyme of monoamines in vertebrates and some invertebrates, was identified in L. cornutus and exhibited substrate specificity for OA compared to 5-HT. Together with the higher enzymatic activity at mid-day compared to dusk, MAO appears to be playing a significant role in regulating the OA and 5-HT signaling in L. cornutus. In conclusion, these results allow a unique preliminary perspective on how OA and 5-HT are influencing the diel shifts in aggression-related behaviors in an ecologically dynamic arthropod.

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Qi, Qin. "An integrative approach to understanding the fitness cost of rifampicin resistance in Pseudomonas aeruginosa". Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:6a82bd64-3b3f-444b-b379-62f01f681594.

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Antibiotic resistance in bacteria is acquired through spontaneous chromosomal mutations or horizontal gene transfer. In the absence of antibiotics, resistant mutants generally show reduced fitness due to compromised growth rate, competitive ability and virulence compared to their antibiotic-sensitive ancestors. The focus of my research is to dissect the molecular underpinnings of the variations in the fitness cost of chromosomal antibiotic resistance using a systems-level approach. From an evolutionary perspective, my research aims are to understand how the fitness cost influences adaptation in resistant populations in an antibiotic-free environment. Using rifampicin resistance in Pseudomonas aeruginosa as a model, my work shows that most of the variation in the fitness cost of rifampicin resistance can be attributed to the direct effect of rifampicin resistance mutations on transcriptional efficiency. Through RNA-Seq transcriptome profiling, I demonstrate that global changes in gene expression levels associated with resistance mutations are surprisingly subtle, suggesting that the transcriptional regulatory network of P. aeruginosa is robust against compromised transcriptional efficiency. Using experimental evolution and whole-genome sequencing, my work reveals a systematic difference in the genetic basis of adaptation in mutants that were propagated in the absence of antibiotics. During compensatory adaptation, resistant mutants can recover the fitness cost of resistance by fixing second-site mutations that directly offset the deleterious effects of resistance mutations. Amongst resistant mutant populations with low fitness costs, general adaptation limits compensatory adaptation, which is most likely to be due to the rarity of compensatory mutations and clonal interference. Far from being the most ubiquitous mechanism in the evolution of resistance, compensatory adaptation is the exception that is more likely to be observed in resistant mutants with high fitness costs. In addition, I applied key elements of the integrative experimental approach developed in this work to dissect the molecular basis of the fitness cost associated with carriage of the pNUK73 small plasmid in P. aeruginosa, which carries the rep gene encoding a plasmid replication protein. My results confirmed that rep expression generates a significant fitness cost in P. aeruginosa and demonstrate how the molecular origins of the fitness cost of resistance can be dissected in a different biological context.

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Dégletagne, Cyril. "Acclimatations des manchots aux contraintes de l’environnement polaire : approches transcriptomique et intégrative sur le manchot Royal (Aptenodytes patagonicus) et le manchot Adélie (Pygoscelis adeliae)". Thesis, Lyon 1, 2011. http://www.theses.fr/2011LYO10348/document.

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King penguins have successfully colonized cold ecosystems of the southern hemisphere by developing physiological mechanisms that are not well understood. The aim of this study was to investigate, at different integrative levels from the gene to the whole animal, the functional responses developed by penguins to overcome polar constrains. We focused on acclimatization mechanisms enabling the first departure to sea of king penguin immatures and the rapid growth of Adélie penguin chicks.To explore differentially expressed genes in pectoralis muscle during penguin’s first sea acclimatization, we used Affymetrix microarrays design for chicken. We first set up and validated a new method to analyze heterologous hybridization transcriptomic profiles. We highlighted a selective shift in metabolic pathways favoring the use of lipids as fuel to sustain highly energetic needs imposed by marine life-style. Our results revealed a development of a global antioxidant response, potential consequences of penguin marine life-style that imposes repeated dives under apnea.Secondly, our integrative study on Adélie penguin’s chick revealed the development of molecular and cellular mechanisms which sustain an original strategy by first allocating most of the energy to growth and then promoting thermogenic processes.Our results showed that both king and Adélie penguins develop complex and coordinated physiological responses to energetic constraints highlighting their high phenotypic plasticity
King penguins have successfully colonized cold ecosystems of the southern hemisphere by developing physiological mechanisms that are not well understood. The aim of this study was to investigate, at different integrative levels from the gene to the whole animal, the functional responses developed by penguins to overcome polar constrains. We focused on acclimatization mechanisms enabling the first departure to sea of king penguin immatures and the rapid growth of Adélie penguin chicks.To explore differentially expressed genes in pectoralis muscle during penguin’s first sea acclimatization, we used Affymetrix microarrays design for chicken. We first set up and validated a new method to analyze heterologous hybridization transcriptomic profiles. We highlighted a selective shift in metabolic pathways favoring the use of lipids as fuel to sustain highly energetic needs imposed by marine life-style. Our results revealed a development of a global antioxidant response, potential consequences of penguin marine life-style that imposes repeated dives under apnea.Secondly, our integrative study on Adélie penguin’s chick revealed the development of molecular and cellular mechanisms which sustain an original strategy by first allocating most of the energy to growth and then promoting thermogenic processes.Our results showed that both king and Adélie penguins develop complex and coordinated physiological responses to energetic constraints highlighting their high phenotypic plasticity

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Nascimento, Leandro Costa do. "Análise de expressão gênica diferencial entre diversas bibliotecas de soja". [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/316766.

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Orientador: Gonçalo Amarante Guimarães Pereira
Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
Made available in DSpace on 2018-08-17T20:48:34Z (GMT). No. of bitstreams: 1 Nascimento_LeandroCostado_M.pdf: 1292421 bytes, checksum: e05cfc27d3bf5ae000bfe8b621a750c8 (MD5) Previous issue date: 2010
Resumo: A soja é uma das principais commodities da economia internacional, sendo sua produção mundial de cerca de 220 milhões de toneladas por safra. Além de ser um alimento rico em proteínas e usado para a fabricação de óleo vegetal, a planta vem ganhando visibilidade devido a possibilidade de ser usada na fabricação de biocombustíveis, principalmente o biodiesel. Para o Brasil, a soja tem grande importância na balança comercial, sendo o país o segundo maior produtor do mundo. Neste contexto, no ano de 2007, o governo brasileiro estabeleceu um consórcio de pesquisas em soja - denominado GENOSOJA - com o objetivo de identificar características genéticas que possam facilitar o processo produtivo da planta, com foco nos diversos estresses que acometem a produção nacional, como a ocorrência de secas, o ataque de pragas e a doença da ferrugem asiática, causada pelo fungo Phakopsora pachyrhizi. Este trabalho está inserido no escopo do GENOSOJA, propondo a construção de bancos de dados contendo informações disponíveis nos diversos bancos públicos (sequências genômicas, ESTs e cDNA full-lenght), integrando-as com as informações geradas no decorrer do projeto (tags de SuperSAGE, bibliotecas subtrativas de cDNA e microRNAs). Além disso, foram construídas diversas interfaces web que oferecem aos usuários diversas funcionalidades, incluindo: comparações estatísticas, consultas por palavras-chave, dados sobre anotação e expressão dos genes nas diversas condições e experimentos estudados. Dessa forma, o ferramental de bioinformática aqui apresentado pode facilitar a compreensão de como as diferenças de expressão gênica da planta podem afetar características de importância agronômica
Abstract: Soybean is one of the main commodities in the international economy, with a world production of about 220 millions of tons per harvest. Besides being a protein rich food and used for vegetable oil production, the plant has been gaining visibility due to the possibility of being to make biofuels, especially biodiesel. The soybean culture is of great importance in the Brazilian economy, being the country the second largest producer in the world. In this context, in 2007, the Brazilian government established a research consortium in soybean - called GENOSOJA - aiming to identify genetic traits that may facilitate the production process of the plant, focusing on the different stresses that affect the national production, as the occurrence of drought, pests' attacks and the asian rust disease, caused by the Phakopsora pachyrhizi fungus. This work is inserted in the GENOSOJA, proposing to build a set of databases containing information available in several public databases (genomic sequences, ESTs and full-length cDNA), integrating them with information generated during the project (SuperSAGE tags, cDNA subtractive libraries and miRNAs). Additionally, several web interfaces were built. They offer to users many features, including: statics comparisons, keyword searches, data about annotation and gene expression in different experiments and conditions. Thus, the bioinformatics tools presented here may facilitate the understanding of how the differences in gene expression can affect plant traits with agronomic importance
Mestrado
Bioinformatica
Mestre em Genética e Biologia Molecular

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Chintapalli, Venkateswara Rao. "An integrative and systems biology approach to Drosophila melanogaster transcriptomes". Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3361/.

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The availability of fully sequenced genomes of the model organisms including Drosophila, and their subsequent annotation has afforded seamless opportunities for reverse genetics in a complex model organism. With the advent of DNA microarrays to assay the levels of tens of thousands of genes in a single sample, functional genomics has been significantly aided to understand the functions in systems context. These microarrays have been employed predominantly on the RNA samples that are extracted from the whole animals for example at different developmental stages or in response to external stimuli. However, these approaches relied on the expression patterns that represent the sum of transcription coming from all the organs, which do not estimate the tissue-specificity of transcription. The purpose of this thesis is to provide tissue-specific transcriptomes of Drosophila melanogaster that were generated as part of the large FlyAtlas project using Affymetrix Drosophila GeneChips® (or microarrays). These chips, one at a time interrogate the levels of 18,500 transcripts (that represent all known genes) using 18,880 distinct probe sets in a single, total RNA sample. For each tissue, four biological replicates were analysed using the chips and the normalised signal intensities were obtained that represent the relative levels of mRNA expression. Using the transcriptomes, a general analysis was performed for potential novel insights into tissue-specific functions (Chintapalli et al., 2007) (Chapter 3). Then, a comparative analysis of epithelial tissues was performed to understand how the epithelia are organised in terms of their transcriptomes (Chapter 4). The Malpighian tubules are the Drosophila epithelial counterparts of the human kidney. They show asymmetric organisation in the body cavity. FlyAtlas segment-specific tubule transcriptomes allowed the comparison of their potential functional similarities and differences, thus to understand the asymmetry in function (Chapter 5)(Chintapalli, 2012). This identified a human Best vitelliform macular dystrophy (BVMD) disease homolog, Best2 in only the anterior pair of tubules that have the morphologically and functionally distinct enlarged initial (or distal) segment, a storage organ for Ca2+. Bestrophins were accordingly selected as candidate genes to analyse organismal functions, and thus to validate previous two theories that implicated bestrophins as Ca2+-activated Clˉ channels and/or Ca2+ channel regulators (Chapter 6). The confocal microscopy analysis of bestrophin YFP fusion proteins revealed interesting and novel localisations of bestrophins, in that Best1 was found in the apical plasma membranes, Best2 localised to peroxisomes, Best3 and Best4 were found intracellular. The salt survival analysis showed that Best1 is essential in regulating extra salt levels in the body. Furthermore, the fluid secretion analysis showed Best1’s potential role in Ca2+-dependent Clˉ function. Interestingly, the flies with reduced levels of Best2 expression showed increased ability to survive on extra salt food; the basis for this was investigated further in Chapter 7. Best2 was also found abundant in the eyes than anywhere else in the head. A comparative analysis of anterior tubule- and eye-specific transcriptomes revealed a potential overlap of Ca2+ signaling components, in that the PLCβ signaling was one. A neuropeptide Ca2+ agonist, capa1 evoked secondary cytosolic Ca2+ responses were found high in Best2 knockdowns. A quantitative PCR (qPCR) analysis of candidate Ca2+ signaling and homeostasis genes in Best2 mutants revealed their gene expression upregulation, under control-fed and salt-fed conditions than their wildtype controls, fed on similar diet regimes. The norpA that encodes PLCβ was found significantly enriched in the mutants. Cyp6a23 is another gene that was highly upregulated in Best2 mutants; it is a Drosophila homologue of human Cyp11b, a Ca2+-responsive gene implicated in renal salt wasting. Upon the downregulation of Cyp6a23, flies became sensitive to salt diet feeding. Other genes investigated and found to be upregulated in the mutants include transient-receptor-potential (trp) Ca2+ channel and retinal degeneration C (rdgC). Together, these results strongly suggest Best2 as a potential Ca2+ channel regulator, and provide fascinating insight into bestrophin function. Peroxisomal localisation of Best2 in line with the implication that peroxisomes act as dynamic regulators of cell Ca2+ homeostasis led to another aspect of the project (Chapter 8). This study identified two peroxins that are most abundant in the tubules and play essential roles in the novel cyclic nucleotide-regulated peroxisomal Ca2+ sequestration and transport pathway and that are detrimental for peroxisome biogenesis and proliferation.

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Mutwil, Marek. "Integrative transcriptomic approaches to analyzing plant co-expression networks". Phd thesis, Universität Potsdam, 2011. http://opus.kobv.de/ubp/volltexte/2011/5075/.

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It is well documented that transcriptionally coordinated genes tend to be functionally related, and that such relationships may be conserved across different species, and even kingdoms. (Ihmels et al., 2004). Such relationships was initially utilized to reveal functional gene modules in yeast and mammals (Ihmels et al., 2004), and to explore orthologous gene functions between different species and kingdoms (Stuart et al., 2003; Bergmann et al., 2004). Model organisms, such as Arabidopsis, are readily used in basic research due to resource availability and relative speed of data acquisition. A major goal is to transfer the acquired knowledge from these model organisms to species that are of greater importance to our society. However, due to large gene families in plants, the identification of functional equivalents of well characterized Arabidopsis genes in other plants is a non-trivial task, which often returns erroneous or inconclusive results. In this thesis, concepts of utilizing co-expression networks to help infer (i) gene function, (ii) organization of biological processes and (iii) knowledge transfer between species are introduced. An often overlooked fact by bioinformaticians is that a bioinformatic method is as useful as its accessibility. Therefore, majority of the work presented in this thesis was directed on developing freely available, user-friendly web-tools accessible for any biologist.
Es ist bereits ausgiebig gezeigt worden, dass Gene, deren Expression auf Transkriptionsebene koordiniert ist, häufig auch funktional in verwandten Stoffwechselwegen vorkommen, und dass sich dies wahrscheinlich auch Spezies- und sogar Reichübergreifend sagen lässt (Ihmels et al., 2004). Anfänglich wurden solche Beziehungen verwendet, um sogenannte Genfunktionsmodule in Hefe und Säugern aufzudecken (Ihmels et al., 2004), um dann orthologe Genfunktionen zwischen verschiedene Spezies und Reichen zu entdecken (Stuart et al., 2003; Bergmann et al., 2004). Modellorganismen wie Arabidopsis werden bevorzugt in der Forschung verwendet, weil man durch die schnelle Generationszeit in kurzer Zeit viele Daten erheben kann und aufgrund dessen die Ressourcen- und Informationsvielfalt um ein Vielfaches größer ist. Ein Hauptziel ist der Wissenstransfer von Modellorganismen auf Spezies, die gesellschaftlich von höherer Bedeutung sind wie z.B. Getreidearten oder andere Feldfrüchte. Pflanzen besitzen oft große Genfamilien und die eindeutige Identifizierung von gut charakterisierten Arabidopsisorthologen in besagten Nutzpflanzen ist kein triviales Vorhaben. In der vorliegenden Arbeit werden Konzepte zur Nutzung von Co-expressionsnetzwerken beschrieben, die helfen sollen (i) Genfunktionen zu identifizieren, (ii) die Organisation von biologischen Prozessen aufzuklären und (iii) das erworbene Wissen auf andere Spezies übertragbar zu machen. Ein häufig von Bioinformatikern übersehender Umstand ist, dass bioinformatische Methoden nur so sinnvoll sind wie ihre Zugänglichkeit. Deshalb basiert der Großteil dieser Arbeit auf freiverfügbaren und vor allem für Biologen nutzerfreundlichen Webtools.

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Tarabichi, Maxime. "Integrative analyses of genome-wide transcriptomic and genomic thyroid cancer profiles". Doctoral thesis, Universite Libre de Bruxelles, 2016. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/225138.

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Cette thèse en bioinformatique a été réalisée entre 2010 et 2015 dans le groupe du Pr. Vincent Detours à l’Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire. Nous avons analysé des données génomiques et transcriptomiques provenant de carcinomes papillaires de la thyroïde (CPTs) et leurs tissus non-cancéreux adjacents. La première partie étudiait les différences transcriptomiques entre CPTs post-Tchernobyl et CPTs sporadiques, et leur tissus non-cancéreux adjacents. Dans notre cohorte, les cas sporadiques étaient en moyenne et significativement un an plus jeunes. Après un ajustement des données transcriptionnelles pour l'âge, près de 400 gènes étaient plus exprimés dans les tissus adjacents des patients exposés aux radiations. Cependant, nous n’avons pu détecter aucune surreprésentation de groupe de gènes participant à des fonctions biologiques connues. Il était possible de distinguer les cas sporadiques des cas post-Tchernobyl sur base des transcriptomes de leurs tissus adjacents, avec une précision de ~70%. Cette surexpression de gènes dans les tissus non-cancéreux adjacents pourrait être liée à une radiosensibilité accrue dans le groupe des patients exposés aux radiations de Tchernobyl. Dans la deuxième étude, nous avons intégré des données provenant des patients de la première partie, incluant les nombres de copies d'ADN des CPTs, le génotype de plus de 400.000 SNPs dans le sang et les données transcriptionnelles des CPTs et leurs tissus non-cancéreux adjacents. En reproduisant les résultats d'une étude précédente, nous avons retrouvé la région 7q11.23 dupliquée exclusivement dans un tiers des patients exposés aux radiations. Dans une étude indépendante, un autre groupe a montré que la duplication de cette région était plus fréquente dans une population de lignées cellulaires radiosensibles que dans la population humaine normale. Cependant, en analysant les transcriptomes des patients présentant cette duplication, nous n'avons pas détecté de différence d’expression des gènes codés dans cette région génomique. En outre, aucun génotype de SNP n'était significativement lié à l'exposition aux radiations. En conclusion, les résultats confirment qu'un tiers des CPTs post-Tchernobyl ont des traces d'un dégât radio-sensibilsant dans leur ADN. Dans une troisième étude, nous avons étudié les différences transcriptionnelles entre CPTs et leurs métastases ganglionnaires (MGs) associées, ainsi qu'entre des CPTs développant des MGs (N+) et des CPTs ne développant pas de MGs (N0). Des études précédentes comparant les MGs et leurs tumeurs associées impliquant d’autres organes ont montré une surexpression de gènes dans les MGs, liés aux cellules immunitaires. Ce signal provient du tissu contaminant environnant les MGs. Pour se défaire de ce signal contaminant, d’autres études ont microdisséqué au laser les parties tumorales des MGs. Cependant, la microdissection retire aussi le stroma associé à la tumeur, alors que celui-ci est justement impliqué dans la progression tumorale. Grâce à une méthode originale, nous avons corrigé nos données d’expression des MGs pour leur contenu en contaminant ganglionnaire non-cancéreux. Après cette correction, l’expression de gènes liés au stroma était plus élevée dans les MGs que dans leurs CPTs. Les différences d’expression entre N0 et N+ n’étaient pas reproductibles entre 4 jeux de données indépendants de CPTs. Ceci démontre l’absence d’un signal transcriptionnelle lié au statut nodal dans ces données. Cependant, en utilisant des données publiques comprenant des centaines de tumeurs, il est possible de prédire le statut nodal (N0 ou N+) des CPTs ainsi que des cancers du sein et du colon à partir de leurs transcriptomes. Des études précédentes montraient des taux de prédiction presque parfaits (>90%) du statut nodal à partir des données transcriptomiques. Nous avons décelés dans ces études le même biais technique de sélection des gènes, qui peut expliquer ces taux artificiellement élevés. Dans notre étude, ce biais n’était pas présent et la précision de nos prédictions était limitée (<70%), questionnant l’intérêt clinique de telles prédictions. La présence d’un signal permettant de prédire le statut nodal et l’irreproductibilité de ce signal dans des jeux de données indépendants peuvent s'expliquer par l’association entre le statut nodal et des caractéristiques d'agressivité des tumeurs, qui pourraient, elles, avoir une influence reproductible sur les transcriptomes. Dans notre dernière étude, nous avons analysé les différences entre CPTs, liées à la présence de BRAFV600E, une mutation commune à 60% des CPTs. En utilisant un jeu de données public, nous avons montré que les CPTs présentant la mutation étaient plus dédifférenciés, et plus infiltrés en stroma, probablement en lymphocytes et fibroblastes; et que ces CPTs présentaient plus de fibrose et proliféraient sans doute plus. Tout ceci suggère que les CPTs mutés pour BRAF constituent un groupe de CPTs plus agressif. Des caractéristiques d’agressivité pourraient être détectées au front invasif, c’est-à-dire la périphérie de la tumeur définissant son contact avec le stroma, notamment la présence de regroupement de cellules isolées du reste de la tumeur. Dans les CPTs, ces îlots cellulaires isolés sont observés sur des lames histologiques 2D et pourraient être expliqués soit par un détachement cellulaire, signe d’agressivité lié au processus métastatique, soit une conformation complexe compatible avec une tumeur connexe en 3D. Dans un CPT, nous avons analysé la conformation 3D du front invasif d'un CPT muté. Nous avons reconstruit son volume 3D grâce à une méthode originale. Les groupes de cellules cancéreuses qui semblaient isolées sur les images 2D d’histopathologie, étaient en fait connectés en 3D. L’hypothèse de la présence de détachement cellulaire suite à la transition épithélio-mésenchymateuse n’est donc pas requise pour expliquer la présence de ces îlots cellulaires en 2D. La forme 3D du front invasif impliquait une surface de contact entre tumeur et stroma bien plus importante qu'impliquée par la forme ellipsoïde habituellement décrite. Les fibroblastes participaient autant à la création de la masse tumorale que les cellules cancéreuses, puisque ces deux groupes de cellules proliféraient à la même vitesse. A l'avenir, le séquençage du matériel génétique de cellules individuelles facilitera notre interprétation des signaux génomiques et transcriptomiques, qui jusqu’alors provenaient de tissu complet, i.e. un mélange de populations de cellules tumorales, stromales et de contaminant. Une signature de radiation pourrait être extraite des profils mutationnels de cellules individuelles exposées aux radiations et à l’H2O2 in vitro et comparée à la signature des CTPs post-Tchernobyl. Les cellules tumorales et stromales individuelles des MGs pourraient être comparées aux cellules tumorales et stromales invividuelles des CPTs. De même les cellules individuelles mutées pour BRAFV600E pourraient être comparées aux cellules non mutées.
Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
info:eu-repo/semantics/nonPublished

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Lin, Tiffany J. "Multinet Bayesian network models for large-scale transcriptome integration in computational medicine". Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/77535.

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Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2012.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 30).
Motivation: This work utilizes the closed loop Bayesian network framework for predictive medicine via integrative analysis of publicly available gene expression findings pertaining to various diseases and analyzes the results to determine which model, single net or multinet, is a more accurate predictor for determining disease status. Results: In general, it is suggested to use the multinet Bayesian network framework for predictive medicine instead of the single net Bayesian network, because for large numbers of samples and features, it is highly likely that it is the stronger predictor, and for smaller numbers of samples and features, if the multinet returns good results, it is likely to be a better predictor than the single net Bayesian network.
by Tiffany J. Lin.
M.Eng.

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Cui, Chenming. "Integrating bioinformatic approaches to promote crop resilience". Diss., Virginia Tech, 2019. http://hdl.handle.net/10919/94424.

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Even under the best management strategies contemporary crops face yield losses from diverse threats such as, pathogens, pests, and environmental stress. Adding to this management challenge is that under current global climate projections these impacts are predicted to become even greater. Natural genetic variation, long used by traditional plant breeders, holds great promise for adapting high performing agronomic lines to these stressors. Yet, efforts to bolster crop plant resilience using wild relatives have been hindered by time consuming efforts to develop genomic tools and/or identify the genetic basis for agronomic traits. Thus, increasing crop plant resilience requires developing and deploying approaches that leverage current high-throughput sequencing technologies to more rapidly and robustly develop genomic tools in these systems. Here we report the integration of bioinformatic and statistical tools to leverage high-throughput sequencing to 1) develop a machine learning approach to determine factors impacting transcriptome assembly and quantitatively evaluate transcriptome completeness, 2) dissect complex physiological pathway interactions in Solanum pimpinellifolium under combined stresses—using comparative transcriptomics, and 3) develop a genome assembly pipeline that can be deployed to rapidly assemble a more contiguous genome, unraveling previously hidden complexity, using Phytopthora capsici as a model. As a result, we have generated strategic guidelines for transcriptome assembly and developed an orthologue and reference free, machine learning based tool "WWMT" to quantitatively score transcriptome completeness from short read data. Secondly, we identified "hub genes" and describe genes involved with "cross-talk" between drought and herbivore stress response pathways. Finally, we demonstrate a protocol for combining long-read sequencing from the Oxford Nanopore Technologies MinION, and short-read data, to rapidly assembly a cost-effective, contiguous and relatively complete genome. Here we uncovered hidden variation in a well-known plant pathogen finding that the genome was 92% bigger than previous estimates with more than 39% of duplicated regions, supporting a hypothesized recent whole genome duplication in this clade. This community resource will support new functional and evolutionary studies in this economically important pathogen.
Doctor of Philosophy
Meeting the food production demands of a burgeoning population in a changing environment, means adapting crop plants to become more resilient to environmental stress. One of the greatest barriers to understanding and predicting crop responses to future environmental change is our poor understanding of the functional and genomic basis of stress resistance traits for contemporary crops. This impediment presents a barrier for rapid crop improvement technologies, such as, gene editing or genomic selection, that is only partially overcome by generating large amounts of sequencing data. Here we need tools that allow us to process and evaluate huge amounts of data generated from next generation sequencing studies to help identify genomic regions associated with agronomic traits. We also need technical approaches that allow us to disentangle the complex genetic interactions that drive plant stress responses. Here we present work that used statistical analysis and recent advances of artificial intelligence to develop a bioinformatic approach to evaluate genomic sequencing data prior to downstream analyses. Secondly, we used a reductionist approach to filter thousands of genes to key genes associated with combined stress responses (herbivory and drought), in the most widely used vegetable in the world, tomato. Finally, we developed a method for generating whole genome sequences that is low-cost and time sensitive and tested it using a well-known plant pathogen genome, wherein we unraveled significant hidden complexity. Overall this work provides community-wide genomic tools and information to promote crop resilience.

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Pagliaro, Sarah Beatriz De Oliveira. "Transcriptional control induced by bcr-abl and its role in leukemic stem cell heterogeneity. Single-Cell Transcriptome in Chronic Myeloid Leukemia: Pseudotime Analysis Reveals Evidence of Embryonic and Transitional Stem Cell States Single Cell Transcriptome in Chronic Myeloid Leukemia (CML): Pseudotime Analysis Reveals a Rare Population with Embryonic Stem Cell Features and Druggable Intricated Transitional Stem Cell States A novel neuronal organoid model mimicking glioblastoma (GBM) features from induced pluripotent stem cells (iPSC) Experimental and integrative analyses identify an ETS1 network downstream of BCR-ABL in chronic myeloid leukemia (CML)". Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASQ032.

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La leucémie myéloïde chronique est une hématopoïèse maligne clonale, caractérisée par l'acquisition de la translocation t (9;22) conduisant au chromosome Ph1 et à son homologue l'oncogène BCR-ABL, dans une cellule souche hématopoïétique très primitive. La LMC est un modèle de thérapies ciblées, car il a été démontré que la preuve de la faisabilité du ciblage de l'activité tyrosine kinase (TK) BCR-ABL à l'aide d'inhibiteurs de TK (TKI) entraîne des réponses et des rémissions majeures. Cependant, les problèmes actuels rencontrés dans ces thérapies sont la résistance des cellules souches leucémiques primitives et leur persistance qui serait liée à l'hétérogénéité des cellules souches au moment du diagnostic, ce qui conduit à la sélection clonale de cellules résistant aux thérapies TKI. J'ai appliqué la technologie de l'analyse du transcriptome des cellule uniques aux cellules de la LMC en utilisant un panel de gènes impliqués dans différentes voies, combinée à l'analyse d'inférence de trajectoire au modèle d'expression des gènes. Les résultats ont montré un état transitoire des cellules souches comprenant des gènes embryonnaires identifiés dans les cellules de la LMC au moment du diagnostic, ce qui pourrait contribuer à la résistance et à la persistance de la LSC. En outre, l'oncoprotéine Bcr-Abl est la tyrosine kinase constitutivement active produite par le gène chimérique BCR-ABL dans la leucémie myéloïde chronique (LMC). Les cibles transcriptionnelles de Bcr-Abl dans les cellules leucémiques n'ont pas été étudiées de manière approfondie. Une expérience de transcriptome utilisant la lignée cellulaire UT7 hématopoïétique exprimant BCR-ABL, a identifié la surexpression du facteur d'élongation eucaryote kinase 2 (eEF2K) qui joue un rôle majeur dans la survie des cellules en cas de privation de nutriments. Dans l'ensemble, les données suggèrent que la surexpression de eEF2K dans la LMC est associée à une sensibilité accrue à la privation de nutriments
Chronic myeloid leukemia is a clonal hematopoietic malignancy, characterized by the acquisition of the t (9;22) translocation leading to Ph1 chromosome and its counterpart BCR-ABL oncogene, in a very primitive hematopoietic stem cell. CML is a model of targeted therapies as the proof of concept of the feasibility of targeting the tyrosine kinase (TK) activity BCR-ABL using TK inhibitors (TKI) has been shown to lead to major responses and remissions. However, the current problems encountered in these therapies are primitive leukemic stem cells resistance and their persistence which is thought to be related to the heterogeneity of the stem cells at diagnosis leading to clonal selection of cells resisting to TKI therapies. I have applied the technology of single cell transcriptome analysis to CML cells using a panel of genes involved in different pathways combined with trajectory inference analysis to the gene expression pattern. The results showed a transitional stem cell states including embryonic genes identified in CML cells at diagnosis which could contribute to LSC resistance and persistence. Furthermore, the oncoprotein Bcr-Abl is the constitutively active tyrosine kinase produced by the chimeric BCR-ABL gene in chronic myeloid leukemia (CML). The transcriptional targets of Bcr-Abl in leukemic cells have not been extensively studied. A transcriptome experiment using the hematopoietic UT7 cell line expressing BCR-ABL, has identified the overexpression of eukaryotic elongation factor kinase 2 (eEF2K) which plays a major role in the survival of cells upon nutrient deprivation. Overall, the data suggest that overexpression of eEF2K in CML is associated with an increased sensitivity to nutrient-deprivation

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Jeanmougin, Marine. "Statistical methods for robust analysis of transcriptome data by integration of biological prior knowledge". Thesis, Evry-Val d'Essonne, 2012. http://www.theses.fr/2012EVRY0029/document.

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Au cours de la dernière décennie, les progrès en Biologie Moléculaire ont accéléré le développement de techniques d'investigation à haut-débit. En particulier, l'étude du transcriptome a permis des avancées majeures dans la recherche médicale. Dans cette thèse, nous nous intéressons au développement de méthodes statistiques dédiées au traitement et à l'analyse de données transcriptomiques à grande échelle. Nous abordons le problème de sélection de signatures de gènes à partir de méthodes d'analyse de l'expression différentielle et proposons une étude de comparaison de différentes approches, basée sur plusieurs stratégies de simulations et sur des données réelles. Afin de pallier les limites de ces méthodes classiques qui s'avèrent peu reproductibles, nous présentons un nouvel outil, DiAMS (DIsease Associated Modules Selection), dédié à la sélection de modules de gènes significatifs. DiAMS repose sur une extension du score-local et permet l'intégration de données d'expressions et de données d'interactions protéiques. Par la suite, nous nous intéressons au problème d'inférence de réseaux de régulation de gènes. Nous proposons une méthode de reconstruction à partir de modèles graphiques Gaussiens, basée sur l'introduction d'a priori biologique sur la structure des réseaux. Cette approche nous permet d'étudier les interactions entre gènes et d'identifier des altérations dans les mécanismes de régulation, qui peuvent conduire à l'apparition ou à la progression d'une maladie. Enfin l'ensemble de ces développements méthodologiques sont intégrés dans un pipeline d'analyse que nous appliquons à l'étude de la rechute métastatique dans le cancer du sein
Recent advances in Molecular Biology have led biologists toward high-throughput genomic studies. In particular, the investigation of the human transcriptome offers unprecedented opportunities for understanding cellular and disease mechanisms. In this PhD, we put our focus on providing robust statistical methods dedicated to the treatment and the analysis of high-throughput transcriptome data. We discuss the differential analysis approaches available in the literature for identifying genes associated with a phenotype of interest and propose a comparison study. We provide practical recommendations on the appropriate method to be used based on various simulation models and real datasets. With the eventual goal of overcoming the inherent instability of differential analysis strategies, we have developed an innovative approach called DiAMS, for DIsease Associated Modules Selection. This method was applied to select significant modules of genes rather than individual genes and involves the integration of both transcriptome and protein interactions data in a local-score strategy. We then focus on the development of a framework to infer gene regulatory networks by integration of a biological informative prior over network structures using Gaussian graphical models. This approach offers the possibility of exploring the molecular relationships between genes, leading to the identification of altered regulations potentially involved in disease processes. Finally, we apply our statistical developments to study the metastatic relapse of breast cancer

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Ranjbar, Niloufar. "Integration of Transcriptomic and Proteomic Data during Nucleus Lobulation of Granulocytes". Master's thesis, Alma Mater Studiorum - Università di Bologna, 2021.

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Nucleus is the origin of most phenotypic activities in a cell. Depending on the cell type, the nucleus can appear in different forms. Mature neutrophils are granulocytic white blood cells with lobulated nucleus that enables them to perform their specialized roles like cell migration in the immune system. Quantitative temporal profiles of human granulocytic cell ensembles of DNA transcripts and proteins, that were previously collected along the process of nuclear deformation, are examined in this thesis. The general aim is to screen the cellular changes during granulocytic differentiation accompanied by nuclear deformation and many other processes. As these transcriptomic and proteomic profiles are hard to interpret due to their large throughput with 10^4 and 10^3 orders of magnitude respectively, bioinformatic data processing including normalization, principal component analysis, differential expression analysis, functional enrichment analysis, and multi-omics integration across datasets, are performed. Granulocytic differentiation associated processes are identified in this study that validate the used experimental model and the data analysis pipeline. Moreover, the cellular functions that were found to be affected during the granulocytic differentiation process could be responsible for nuclear deformation, its downstream processes, or just independent processes occurring in parallel. As nuclear deformation is a relatively new field of research, it is not annotated in the available biological databases and as a result, the nuclear deformation category was not found by the functional enrichment analysis. However, some categories related to nuclear activities and a general accordance in RNA-protein regulation were found that represent interesting directions to be pursued in future studies after this first screening. Finally, this thesis leads the way towards discovering the mechanism of nuclear deformation in the process of differentiating the cells into neutrophils.

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Ganief, Tariq Ahmad. "A network analysis based proteomic and transcriptomic investigation into HIV-Tat induced neuronal dysfunction and the neuroprotective effect of lithium". Doctoral thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/22759.

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HIV-associated neurocognitive disorders (HAND) affect up to 70% of HIV positive individuals and are the leading cause of dementia in patients under 40 years. Despite this, the molecular mechanisms involved in the onset of HAND are not well understood. Among a number of plausible etiological agents of HAND, HIV-Tat has been shown to be neurotoxic in vitro and in vivo, but the basis of its induced neuronal dysregulation remains relatively poorly characterised, giving rise to various competing theories. This thesis describes differential, quantitative proteomic analyses of HIV-Tat-treated neuronal cells in vitro, the goal being to gain deeper insight into the underlying molecular basis of this HIV-Tat-mediated dysregulation, as well as to potentially inform better patient treatments in the future. To achieve this goal, deep, quantitative proteomic analysis of HIV-Tat treated SILAC-labelled SH-SY5Y neuroblastoma cells was carried out, alongside transcriptomic analysis of the same system in which 3077 proteins were identified and quantified with 407 proteins and 1074 genes being differentially expressed. Subsequently, label-free proteomics analysis was used to study the ability of lithium - a proposed new treatment for HAND - to suppress the HIV-Tat induced dysregulated molecular phenotype in SH-SY5Y cells in which 3757 were identified and quantified with 360 and 531 being significantly differentially expressed in HIV-Tat and HIV-Tat + lithium treated cells, respectively.

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Oerton, Erin. "Understanding disease and disease relationships using transcriptomic data". Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/289128.

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As the volume of transcriptomic data continues to increase, so too does its potential to deepen our understanding of disease; for example, by revealing gene expression patterns shared between diseases. However, key questions remain around the strength of the transcriptomic signal of disease and the identification of meaningful commonalities between datasets, which are addressed in this thesis as follows. The first chapter, Concordance of Microarray Studies of Parkinson's Disease, examines the agreement between differential expression signatures across 33 studies of Parkinson's disease. Comparison of these studies, which cover a range of microarray platforms, tissues, and disease models, reveals a characteristic pattern of differential expression in the most highly-affected tissues in human patients. Using correlation and clustering analyses to measure the representativeness of different study designs to human disease, the work described acts as a guideline for the comparison of microarray studies in the following chapters. In the next chapter, Using Dysregulated Signalling Paths to Understand Disease, gene expression changes are linked on the human signalling network, enabling identification of network regions dysregulated in disease. Applying this method across a large dataset of 141 common and rare diseases identifies dysregulated processes shared between diverse conditions, which relate to known disease- and drug-sharing-relationships. The final chapter, Understanding and Predicting Disease Relationships Through Similarity Fusion, explores the integration of gene expression with other data types - in this case, ontological, phenotypic, literature co-occurrence, genetic, and drug data - to understand relationships between diseases. A similarity fusion approach is proposed to overcome the differences in data type properties between each space, resulting in the identification of novel disease relationships spanning multiple bioinformatic levels. The similarity of disease relationships between each data type is considered, revealing that relationships in differential expression space are distinct from those in other molecular and clinical spaces. In summary, the work described in this thesis sets out a framework for the comparative analysis of transcriptomic data in disease, including the integration of biological networks and other bioinformatic data types, in order to further our knowledge of diseases and the relationships between them.

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Marquez-Quinones, Adriana. "Reactive oxygen species, hepatitis and carcinogenesis initiation : an integrative approach combining transcriptomic and metabonomic profilings". Toulouse, INSA, 2007. http://eprint.insa-toulouse.fr/archive/00000181/.

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Le stress oxydant et l’inflammation jouent un rôle important dans le développement du cancer. Les modèles animaux, comme le rat LEC, qui est muté sur un gène en relation avec l’excrétion hépatique du cuivre et qui développe spontanément une hépatite puis un carcinome hépatocellulaire, sont des outils intéressants pour comprendre la relation existant entre inflammation, stress oxydant et initiation du cancer. L’expression des gènes et les profils métaboliques des rats LEC à différentes étapes de l’hépatite ont donc été comparés à ceux de rats LEC contrôles, traités par un chélateur du cuivre, de façon à pouvoir mettre en évidence les familles de gènes et les ensembles métaboliques impliqués dans l’inflammation et l’initiation de la cancérogenèse hépatiques. Les analyses statistiques multivariées, couplées à l’utilisation des bases de données d’ontologie des gènes a permis de mettre en évidence une sur-représentation et une augmentation de l’expression des gènes impliqués dans le protéasome avec l’hépatite. Cependant, certaines activités du protéasome ont été parallèlement diminuées. L’hypothèse de l’intervention du protéasome dans la pathogenèse de l’hépatite est nouvelle. Les analyses métabonomiques réalisées à partir des profils 1H-RMN urinaires et hépatiques ont permis d’identifier des métabolites associés au développement de l’hépatite. De plus, grâce à une régression PLS2, nous avons établi une relation canonique entre les données transcriptomiques et métabonomiques du foie. La relation linéaire obtenue entre les deux jeux de données a montré que l’expression des gènes et les perturbations métaboliques pouvaient être corrélées en fonction du développement de l’hépatite. Ces données corrélées pourront servir à formuler d’autres hypothèses concernant les mécanismes impliqués dans le développement de l’hépatite et du cancer du foie. Ce travail constitue une approche originale et fonctionnelle qui illustre la puissance des analyses statistiques multivariées pour analyser les données provenant des technologies en omique et qui permet de formuler des hypothèses rationnelles
Oxidative stress and inflammation play an important role in the development of cancer. Animal models, such as LEC rats, which have a mutation related to hepatic copper excretion and develop spontaneously an hepatitis and a subsequent hepatocellular carcinoma, are useful tools to study the relationship between oxidative stress, inflammation and initiation of cancer. Gene expression and metabolic profiles of LEC rats at different stages of hepatitis were compared to those of control LEC rats treated with a copper chelating agent, to evaluate the different gene families and metabolic networks involved in liver inflammation and carcinogenesis initiation. Multivariate statistical analyses coupled to gene ontology classification of transcriptomic data revealed an overrepresentation and an increase in the expression of genes involved in protein metabolism-related functions, mainly proteasome genes, with hepatitis. However, some proteasome activities were decreased at the same time. Involvement of proteasome in hepatitis pathogenesis is a new hypothesis. Metabonomic analyses done on 1H NMR profiles from urine and liver samples allowed to identify some metabolites related to hepatitis development. PLS2 regression was made to determine a canonical relationship between liver metabonomic and transcriptomic data. The linear correlation obtained indicated that both gene expression and metabolic perturbations are closely related face to hepatitis development. These correlated data will help making new hypotheses for mechanisms involved in liver inflammation and cancer. We present here an integrative analysis of hepatitis development and cellular responses due to oxidative stress. Our work shows an original and functional way of analysis that illustrates the power of multivariate statistical tools to explore omic data and to raise rational biological hypothesis

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Garcia, Maxime. "Découverte de biomarqueurs prédictifs en cancer du sein par intégration transcriptome-interactome". Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM4109/document.

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L’arrivée des technologies à haut-débit pour mesurer l’expression des gènes a permis l’utilisation de signatures génomiques pour prédire des conditions cliniques ou la survie du patient. Cependant de telles signatures ont des limitations, comme la dépendance au jeu de données d’entrainement et le manque de généralisation. Nous proposons un nouvel algorithme, Integration Transcriptome-Interactome (ITI) (Garcia et al.) pour extraire une signature generalisable prédisant la rechute métastatique dans le cancer du sein par superimposition d’un très large jeu de données d’interaction protèine-protèine sur de multiples jeux de données d’expression des gènes. Cette méthode ré-implemente l’algorithme Chuang et al. , avec la capacité supplémentaire d’extraire une signature génomique à partir de plusieurs jeux de donnés d’expression des gènes simultanément. Une analyse non-supervisée et une analyse supervisée ont été réalisés sur un compendium de jeux de donnés issus de puces à ADN en cancer du sein. Les performances des signatures trouvées par ITI ont été comparé aux performances des signatures préalablement publiées (Wang et al. , Van De Vijver et al. , Sotiriou et al. ). Nos résultats montrent que les signatures ITI sont plus stables et plus généralisables, et sont plus performantes pour classifier un jeu de données indépendant. Nous avons trouvés des sous-réseaux formant des complexes précédement relié à des fonctions biologiques impliquées dans la nétastase et le cancer du sein. Plusieurs gènes directeurs ont été détectés, dont CDK1, NCK1 et PDGFB, certains n’étant pas déjà relié à la rechute métastatique dans le cancer du sein
High-throughput gene-expression profiling technologies yeild genomic signatures to predict clinical condition or patient outcome. However, such signatures have limitations, such as dependency on training set, and lack of generalization. We propose a novel algorithm, Interactome-Transcriptome Integration (ITI) (Garcia et al.) extract a generalizable signature predicting breast cancer relapse by superimposition of a large-scale protein-protein interaction data over several gene-expression data sets. This method re-implements the Chuang et al. algorithm, with the added capability to extract a genomic signature from several gene expression data sets simultaneously. A non-supervised and a supervised analysis were made with a breast cancer compendium of DNA microarray data sets. Performances of signatures found with ITI were compared with previously published signatures (Wang et al. , Van De Vijver et al. , Sotiriou et al. ). Our results show that ITI’s signatures are more stable and more generalizable, and perfom better when classifying an independant dataset. We found that subnetworks formed complexes functionally linked to biological functions related to metastasis and breast cancer. Several drivers genes were detected, including CDK1, NCK1 and PDGFB, some not previously linked to breast cancer relapse

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Jäger, Günter [Verfasser], i Kay [Akademischer Betreuer] Nieselt. "Advanced Visual Analytics Approaches for the Integrative Study of Genomic and Transcriptomic Data / Günter Jäger ; Betreuer: Kay Nieselt". Tübingen : Universitätsbibliothek Tübingen, 2016. http://d-nb.info/1164168916/34.

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Jäger, Günter Verfasser], i Kay [Akademischer Betreuer] [Nieselt. "Advanced Visual Analytics Approaches for the Integrative Study of Genomic and Transcriptomic Data / Günter Jäger ; Betreuer: Kay Nieselt". Tübingen : Universitätsbibliothek Tübingen, 2016. http://d-nb.info/1164168916/34.

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GERVASONI, FEDERICA. "DEVELOPMENT OF BIOINFORMATIC METHODS FOR THE INTEGRATION OF TRANSCRIPTOMIC AND EPIGENOMIC ANALYSIS OF COLORECTAL CANCER DERIVED ORGANOIDS". Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/810878.

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Cancer is characterized by pervasive epigenetic alterations with enhancer dysfunction as a key driver of tumor transcriptional deregulation and dependencies. In this work, we seek to unravel the chromatin landscape of human colorectal cancer (CRC) by exploiting the organoid model in order to identify a common epigenetic blueprint and investigate its relevance in other types of cancers. To this extent, we generated a library of patient-derived organoids (PDOs) from different subtypes of CRC representing the heterogeneity of this type of tumor. We reconstructed the epigenetic landscape of CRC and retrieved a catalog of regulatory elements using a complete panel of the most common histone modifications. Next, we identified a conserved and tumor-specific enhancerome that is cancer cell-intrinsic and independent of interpatient tumor heterogeneity. Interestingly, we also identified the transcriptional co-activator YAP and TAZ as key regulators of the conserved CRC gained enhancerome. Reaching beyond CRC, we took advantage of ATAC-seq data of diverse tumor malignancies to demonstrate that our CRC enhancer blueprint was a conserved feature of epigenetic deregulation in human cancer pathology. We next sought to depict the cancer epigenetic deregulation at single-cell resolution demonstrating the specificity of our cancer regulatory blueprint for malignant cells in different types of cancer, suggesting a key role of the cancer regulatory blueprint in tumorigenesis and maintenance of the cancer cell state. Despite the considerable genetic and clinical heterogeneity of CRC, our work suggests a common layer of YAP/TAZ-mediated epigenetic deregulation in cancer and provides a detailed epigenetic resource of critical importance for identifying therapeutic targets with enhanced precision.

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Monot, Clément. "La particule ribonucléoprotéique de l'élément L1 humain : spécificité de l'activité transcriptase inverse et partenaires cellulaires". Thesis, Nice, 2013. http://www.theses.fr/2013NICE4062.

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Les éléments LINE-1 (L1) sont les seuls éléments transposables autonomes et actifs, constituant 20% de notre ADN. Ils prolifèrent via un intermédiaire ARN dans un processus appelé rétrotransposition. Les L1s encodent deux protéines, ORF1p et ORF2p, qui s’associent avec l’ARN du L1 pour former une particule ribonucléoprotéique (RNP), constituant l’intermédiaire fonctionnel de la rétrotransposition. Les L1s « sautent » activement dans les cellules germinales, les cellules souches embryonnaires et dans l’embryon précoce, conduisant occasionnellement à des maladies génétiques. Ils sont également exprimés et mobiles dans un certain nombre de cancers. Les sites d’intégration des L1s sont généralement considérés comme aléatoires, les déterminants moléculaires de leur insertion demeurant mal connus. Afin d’éclaircir ce processus, nous avons d’abord exploré les propriétés biochimiques des RNPs du L1, en mesurant leur activité transcriptase inverse in vitro sur une collection variée de substrats d’ADN. Nous avons observé que des substrats, qui diffèrent par leur séquence ou leur structure, ne sont pas tous utilisés efficacement par les RNPs du L1 pour amorcer la transcription inverse. Notre travail suggère que la spécificité et la flexibilité de l’initiation de la transcription inverse du L1 participe aux choix du site d’insertion. Dans un second temps, nous avons recherché des partenaires cellulaires de la RNP du L1 qui pourraient contribuer à la rétrotransposition et/ou la réguler, par des cribles double-hybride chez la levure. Nous avons découvert que la protéine ORF2p interagit avec un groupe de récepteurs nucléaires. Ces derniers possèdent un domaine de liaison à l’ADN qui reconnaît des séquences d’ADN spécifiques réparties dans le génome, et un domaine de liaison du ligand, qui permet d’activer la transcription des gènes cibles. Nos données suggèrent que ces facteurs participent à la rétrotransposition des L1s, possiblement en ciblant leurs RNPs dans certaines régions du génome. Dans leur ensemble, nos travaux ont contribué à améliorer notre compréhension de la relation entre éléments transposables et génome hôte, et de leur impact sur la plasticité du génome humain
LINE-1 (L1) elements are mobile genetic elements, comprising up to 20% of the contemporary human genome, in which they are the only autonomously active element. They replicate through an RNA intermediate in a process named retrotransposition. Replication-competent L1 copies code for two proteins, ORF1p and ORF2p, that associate in cis with their own RNA to form a ribonucleoprotein complex (RNP), the functional intermediate of retrotransposition. L1s « jump » actively in germ cells, embryonic stem cells and in the early embryo, leading occasionally to genetic diseases. These elements are also expressed and mobile in a number of cancers. L1 insertion sites are generally considered as random. The molecular determinants of L1 insertion, as well as many steps of the retrotransposition cycle, remain uncertain. To get further insight in the molecular mechanisms of L1 retrotransposition, we first explored the biochemical properties of the L1 RNP, by measuring their reverse transcriptase activity in vitro on various DNA substrates. Using this approach, we observed that L1 RNPs do not equally extend DNA substrates, which differ in sequence or structure, to initiate cDNA synthesis. Our work suggests that the specificity and flexibility of L1 reverse transcription priming contribute to the choice of target sites. In a second approach, we performed yeast two-hybrid screens in order to discover cellular partners of the L1 RNP, which could contribute and/or regulate retrotransposition, We found that ORF2p interacts with a group of nuclear receptors. These proteins contain a DNA binding domain, which recognizes specific DNA sequences spread in the genome, and a ligand binding domain, driving transcriptional regulation of target genes. Our data suggest that these factors participate to L1 retrotransposition, potentially by tethering L1 RNPs to specific genomic regions. Altogether, this work has contributed to a better understanding of the relationship between mobile genetic elements and their host genome, and their impact on human genome plasticity

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PATRIZI, SARA. "Multi-omics approaches to complex diseases in children". Doctoral thesis, Università degli Studi di Trieste, 2022. http://hdl.handle.net/11368/3015193.

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Le tecnologie “-omiche” studiano l’insieme delle molecole presenti nel campione biologico di interesse, in maniera completamente agnostica. L’integrazione di diversi tipi di dati omici, chiamata “multi-omica” o “omica verticale”, fornisce indicazioni importanti su come le cause di una malattia portano alle sue conseguenze funzionali. Queste indicazioni sono particolarmente utili nel caso delle malattie complesse, che sono causate dall’interazione di vari fattori genetici e regolatori con vari contributi ambientali. In questo lavoro, degli approcci multi-omici appropriati sono stati applicati a due malattie complesse che di solito iniziano a manifestarsi durante l’infanzia, hanno un’incidenza crescente, e hanno vari elementi sconosciuti nella loro patologia molecolare, ovvero le malformazioni polmonari congenite e la celiachia. Gli scopi dei due progetti sono, rispettivamente, di verificare se nel tessuto polmonare malformato ci sono varianti genetiche o alterazioni della metilazione del DNA associate al cancro, e di trovare alterazioni comuni nel metiloma e nel trascrittoma di cellule epiteliali dell’intestino tenue di bambini affetti da celiachia. Per quanto riguarda i metodi, nel progetto sulle malformazioni polmonari sono stati usati microarray di metilazione whole genome e sequenziamento dell’intero genoma, mentre nel progetto sulla celiachia sono stati usati microarray di metilazione whole genome e sequenziamento dell’mRNA totale. In tutte le 20 malformazioni polmonari incluse nello studio sono state trovate regioni differenzialmente metilate in geni probabilmente legati al cancro del polmone. Inoltre, 5 campioni malformati avevano almeno una variante somatica missenso in un gene noto come driver del tumore del polmone, e 5 altri campioni avevano un totale di 2 delezioni di oncosoppressori driver del tumore del polmone e 10 amplificazioni di oncogeni driver del tumore del polmone. Questi dati suggeriscono che le malformazioni polmonari congenite possono avere alterazioni genetiche ed epigenetiche di tipo pre-maligno, la cui presenza è impossibile da prevedere sulla base delle sole informazioni cliniche. Nel secondo progetto, una Principal Component Analysis dei dati di metilazione ha mostrato che i pazienti celiaci si dividono in due cluster, di cui uno si sovrappone ai controlli. 174 geni erano differenzialmente metilati rispetto ai controlli in entrambi i cluster. Una Principal Component Analysis dei dati di espressione genica (mRNA-Seq) ha mostrato una distribuzione simile a quella dei dati di metilazione, e 442 geni erano differenzialmente espressi in entrambi i cluster. Sei geni, principalmente coinvolti nella risposta interferonica e nel processo di processamento e presentazione degli antigeni, erano sia differenzialmente espressi che differenzialmente metilati in entrambi i cluster. Questi risultati indicano che le cellule epiteliali dell’intestino tenue di bambini affetti da celiachia sono altamente variabili da un punto di vista molecolare, ma condividono delle differenze fondamentali che le rendono in grado di rispondere agli interferoni e di processare e presentare antigeni con maggiore efficienza rispetto ai controlli. Nonostante le loro limitazioni, gli studi presentati mostrano che degli approcci multi-omici specifici possono essere usati per rispondere alle domande ancora aperte riguardo a diverse malattie, studiando più funzioni cellulari contemporaneamente e spesso portando anche alla generazione di nuove ipotesi e a scoperte inaspettate.
“-Omic” technologies can detect the entirety of the molecules in the biological sample of interest, in a non-targeted and non-biased fashion. The integration of multiple types of omics data, known as “multi-omics” or “vertical omics”, can provide a better understanding of how the cause of disease leads to its functional consequences, which is particularly valuable in the study of complex diseases, that are caused by the interaction of multiple genetic and regulatory factors with contributions from the environment. In the present work appropriate multi-omics approaches are applied to two complex conditions that usually first manifest in childhood, have rising incidence and gaps in the knowledge of their molecular pathology, specifically Congenital Lung Malformations and Coeliac Disease. The aims are, respectively, to verify if cancer-associated genomic variants or DNA methylation features exist in the malformed lung tissue and to find common alterations in the methylome and the transcriptome of small intestine epithelial cells of children with CD. The methods used in the Congenital Lung Malformations project are Whole Genome Methylation microarrays and Whole Genome Sequencing, and for the Coeliac Disease the whole genome methylation microarrays and mRNA sequencing. Differentially methylated regions in possibly cancer-related genes were found in each one of the 20 lung malformation samples included. Moreover, 5 malformed samples had at least one somatic missense single nucleotide variant in genes known as lung cancer drivers, and 5 malformed samples had a total of 2 deletions of lung cancer driver tumour suppressor and 10 amplifications of lung cancer driver oncogenes. The data showed that congenital lung malformations can have premalignant genetic and epigenetic features, that are impossible to predict with clinical information only. In the second project, Principal Component Analysis of the whole genome methylation data showed that CD patients divide into two clusters, one of which overlaps with controls. 174 genes were differentially methylated compared to the controls in both clusters. Principal Component Analysis of gene expression data (mRNA-Seq) showed a distribution that is similar to the methylation data, and 442 genes were differentially expressed in both clusters. Six genes, mainly related to interferon response and antigen processing and presentation, were differentially expressed and methylated in both clusters. These results show that the intestinal epithelial cells of individuals with CD are highly variable from a molecular point of view, but they share some fundamental differences that make them able to respond to interferons, process, and present antigens more efficiently than controls. Despite the limitations of the present studies, they have shown that targeted multi-omics approaches can be set up to answer the relevant disease-specific questions by investigating many cellular functions at once, often generating new hypotheses and making unexpected discoveries in the process.

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Junior, Milton Yutaka Nishiyama. "Desenvolvimento da plataforma CaneRegNet para anotação funcional e análises do transcriptoma da cana-de-açúcar". Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/95/95131/tde-28032016-154802/.

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A identificação de genes alvos, vias de sinalização e vias metabólicas para melhoramento de cana-de-açúcar associados a características de interesse, ainda são pouco conhecidos e estudados. Alguns estudos do transcriptoma através de plataformas de microarranjo têm buscado identificar listas de genes, para experimentos tecido- específico ou submetidos a condições de estresse bióticos e abióticos. Estudos pontuais destes dados tem sido associados a vias metabólicas ou vias de sinalização já descritas na literatura, de forma a identificar alterações relacionadas a padrões de expressão gênica. Porém, estas relações em cana-de-açúcar são pouco conhecidas e estudadas. O estudo e entendimento de cana-de-açúcar por meio da diversidade genética e de sua adaptação ao ambiente é um grande desafio, principalmente pela ausência de um genoma sequenciado e por possuir um genoma complexo. Apresentamos nossos resultados para tentar superar tais limitações e desafios para estudos de expressão gênica. Foram desenvolvidas metodologias para anotação funcional do transcriptoma, centradas na transferência de anotação, identificação de vias metabólicas e enzimas pelo método de similaridade bi-direcional, predição de genes full-length, análises de ortologia e desenho de oligonucleotídeos para microarranjos customizados, resultando no ORFeoma de cana-de-açúcar, na identificação e classificação de famílias de fatores de transcrição e identificação de genes ortólogos entre gramíneas. Além disso, desenvolvemos uma plataforma para processamento e análise automatizada de experimentos por microarranjo, para armazenamento, recuperação e integração com a anotação funcional. Adicionalmente desenvolvemos e implementamos métodos para seleção de genes diferencialmente e significativamente expressos, e abordagens para análise de enriquecimento de categorias, e escores de atividade de vias metabólicas. De forma a integrar a anotação funcional do transcriptoma aos estudos por expressão gênica, desenvolvemos a plataforma CaneRegNet e uma interface para integração desta rede de dados biológicos e conhecimentos, composta por aplicativos para consulta e prospecção de dados por análises de agrupamento e correlação entre experimentos de microarranjo, possibilitando a geração de novas hipóteses e predições dentro da organização da regulação celular.
The identification of target genes, metabolic and signaling pathways associated with characteristics of interest to the sugarcane improvement are still poorly known and studied. Some transcritptome studies through microarray platforms has tried to identify lists of genes, for tissue-specific experiments or subjected to conditions of biotic and abiotic stress. In the literature specific studies of these data has already been associated with metabolic or signaling pathway, in order to identify changes in these tracks related to patterns of gene expression. However, these relations are still little know and generally defined slightly. The study and understanding of sugarcane by means of genetic diversity and its adaptation to the environment is a major challenge, mainly due to the absence of a sequenced genome and by your complex genome. We present our results to surpass this barrier e challenges for the study of gene expression. Methodologies were developed for the transcriptome functional annotation, focused on the annotation transfer, identification of metabolic pathways and enzymes by the bi- directional method; prediction of full-length genes; ortology analysis and probe design for customized microarrays, resulting in the sugarcane ORFeome, the identification and classification of transcription factor families and identification of ortholog genes between grasses. Besides that, we have developed a plataform for automated processing and analysis for microarray experiments, to store, retrieve and integration with the functional annotation. Additionally, we have developed and implemented methods for identification of differentially and significantly expressed genes, and approaches for over-represented analysis and functional class scoring (FCS). To integrate the functional annotation and the studies by gene expression profile, we have developed the CaneRegNet platform and an interface to integrate this network of biological data and knowledge, composed by searching and data mining tools for clustering and correlations between microarray experiments, enabling the generation of new hypothesis and predictions around the organization of cellular regulation.

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Hetti, Arachchilage Madara Dilhani. "Coevolution of epitopes in HIV-1 pre-integration complex proteins: protein-protein interaction insights". Kent State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=kent1530646538935895.

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Ranawaka, Ranawaka Arachchige Gayana Buddhini. "The organisation and epigenetic landscape of the Nicotiana benthamiana genome". Thesis, Queensland University of Technology, 2022. https://eprints.qut.edu.au/230497/8/Buddhini_Ranawaka_Thesis.pdf.

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The thesis constitutes an original contribution to our understanding of the genome, transcriptome, epigenome, and metabolomic features of two evolutionarily distinct ecotypes of Nicotiana benthamiana (native Australian tobacco). It investigates multi-omics data to comprehend their contribution to the distinct morphological features, the significance in the context of its key role in plant biotechnology, and their links to its evolutionary past.

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Xia, Yao. "Artificial intelligence-assisted prediction, feature selection, and multi-omics integration in exploring the interaction between IgG N-glycome and transcriptome and constructing the ageing clock". Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2023. https://ro.ecu.edu.au/theses/2646.

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Gay, Virginie. "Analyse des réponses cellulaires induites par l’intégration d’un ADN étranger au sein du génome". Thesis, Lyon 1, 2010. http://www.theses.fr/2010LYO10201/document.

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Il existe un certain nombre de situations au cours desquelles l’intégrité du génome cellulaire est mise en danger. Ceci se produit notamment lors de mouvements de gènes (translocation, éléments mobiles), lors d’infections virales parfois intégratives (AAV, HBV, HPV) ou lors d’infections rétrovirales. En effet, le cycle de réplication des rétrovirus nécessite une étape d’intégration du génome viral dans l’ADN génomique de la cellule infectée. Malgré les nombreuses études menées sur les infections par le VIH, les cancers viro-induits ou non et les thérapies géniques basées sur les rétrovirus, aucune donnée n’est actuellement disponible sur les modifications cellulaires induites par de telles perturbations chromosomiques. L’objectif du projet était d’identifier des mécanismes cellulaires induits par des atteintes à l’intégrité du génome, plus précisément par l’insertion de molécules d’ADN non cellulaire dans les chromosomes. L’intégration de matériel génétique additionnel a été induite par des vecteurs lentiviraux dérivés du VIH-1. Les modifications cellulaires uniquement dues à l’intégration ont été isolées par comparaison de vecteurs intégratif et non intégratif. Des cellules primaires du derme humain ont été sélectionnées pour l’étude. Les temps post infection et les doses virales les plus adéquates ont été sélectionnés grâce à des expériences de cinétiques d’intégration couplées à une quantification des ADN viraux intégrés. L’analyse des modifications cellulaires induites par l’intégration de l’ADN étranger a portée sur l’ensemble du transcriptome et sur l’ensemble du protéome cellulaire. Dans le but d’effectuer une analyse transcriptomique, des puces à ADN, représentant le génome humain complet, ont été utilisées. Cette étude a démontré une forte répression transcriptionnelle induite par l’intégration. De plus, toutes les fonctions cellulaires sont perturbées par le processus. Finalement, une classification par interactions et fonctions biologiques a mis en évidence cinq processus cellulaires majoritairement affectés par l’intégration de l’ADN étranger, qui correspondent au cycle et à la mort cellulaire, au remodelage et à la réparation de la chromatine et à la réponse immunitaire ou au stress. Dans le but de compléter cette analyse transcriptomique, une étude protéomique a été réalisée. Les protéines cellulaires ont été séparées sur des gels bi-dimensionnels. Parmi les neuf protéines identifiées en spectrométrie de masse, certaines appartiennent au cytosquelette et d’autres aux mécanismes de réponse au stress. L’intégration d’un ADN étranger au sein du génome provoque donc bien des perturbations cellulaires. L’intégration de matériel génétique additionnel ne concernant pas seulement les rétrovirus, les données obtenues lors de cette étude pourront permettre (i) de développer des stratégies de défenses contre les rétrovirus ou contre les autres maladies caractérisées par des atteintes à l’intégrité du génome, (ii) d’évaluer les risques encourus par l’intégration d’un vecteur thérapeutique dans le génome cellulaire lors des thérapies géniques ou des expériences de transfert de gènes
In numerous situations, cell genome integrity could be in danger. This is the case during gene movements (translocations, mobiles elements), during viral infections that could be sometimes integrative (AAV, HBV, HPV) or during retroviral infections. Indeed, the replication cycle of retroviruses requires a viral genome integration step. In spite of the studies on HIV infections, viral or non viral cancers and retrovirus-based gene therapy, no data are available concerning the cellular modifications induced by such chromosomal disruptions. The aim of work was to identify cellular mechanisms induced by the insertion of a non cellular DNA into the chromosomes. The integration of additional DNA was provoked by HIV-1-based lentiviral vectors. Cellular modifications only due to the integration step were isolated by comparison of integrative and non integrative vectors. Primary human dermal fibroblasts cells were selected for the study. Optimal times post infection and viral quantities were defined using kinetic integration experiments and integrated viral DNA quantifications. The study of cellular modifications induced by the integration of the foreign DNA was applied on the cellular global transcriptome and proteome. In order to perform a transcriptomic analyses, DNA microarray corresponding to the whole human genome, were used. This study revealed a strong transcriptional repression induced by the integration. Moreover, every cellular function are disturbed by the process. Finally, a network based on molecular interactions and biological functions underlined five cellular processes mostly affected by the foreign DNA integration and corresponding to the cell cycle and death, the remodelling and repair of chromatin and the immunity or stress responses. To complete this transcriptomic analyses, a proteomic study was realized. Cellular proteins were separated on 2D gels. Among the nine proteins identified by mass spectrometry, some are linked to the cytoskeleton and other to the cellular stress. Thus, integration of a foreign DNA into the genome provoked cellular perturbations. As additional DNA integration do not only concern retroviruses, data obtained during this study could allow (i) the development of defensive strategies against retroviruses or other diseases implicating the genome integrity and (ii) the evaluation of risks linked to the integration of a therapeutic vector into the genome during gene therapy and gene transfer experiments

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Metzner, Ernst Michael [Verfasser], Patrick [Akademischer Betreuer] Schweizer, Ralph [Akademischer Betreuer] Hückelhoven i Karin D. [Akademischer Betreuer] Breunig. "Barley infected by powdery mildew : host transcriptome and proteome changes and the integration of both data sets / Ernst Michael Metzner. Betreuer: Patrick Schweizer ; Ralph Hückelhoven ; Karin D. Breunig". Halle, Saale : Universitäts- und Landesbibliothek Sachsen-Anhalt, 2012. http://d-nb.info/1025352505/34.

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Wachter, Astrid [Verfasser], Tim [Akademischer Betreuer] [Gutachter] Beißbarth i Edgar [Gutachter] Wingender. "Data Integration of High-Throughput Proteomic and Transcriptomic Data based on Public Database Knowledge / Astrid Wachter ; Gutachter: Tim Beißbarth, Edgar Wingender ; Betreuer: Tim Beißbarth". Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2017. http://d-nb.info/1132336767/34.

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Crispatzu, Giuliano [Verfasser], Michael [Gutachter] Nothnagel, Bernd [Gutachter] Wollnik, Joachim [Gutachter] Krug i Holger [Gutachter] Thiele. "Integrative approaches to high-throughput data in lymphoid leukemias (on transcriptomes, the whole-genome mutational landscape, flow cytometry and gene copy-number alterations) / Giuliano Crispatzu ; Gutachter: Michael Nothnagel, Bernd Wollnik, Joachim Krug, Holger Thiele". Köln : Universitäts- und Stadtbibliothek Köln, 2017. http://d-nb.info/1141904438/34.

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Sitte, Maren [Verfasser], Tim [Akademischer Betreuer] Beißbarth, Tim [Gutachter] Beißbarth i Stephan [Gutachter] Waack. "Network Based Integration of Proteomic and Transcriptomic Data: Study of BCR and WNT11 Signaling Pathways in Cancer Cells / Maren Sitte ; Gutachter: Tim Beißbarth, Stephan Waack ; Betreuer: Tim Beißbarth". Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2020. http://d-nb.info/1210264773/34.

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LOVINO, MARTA. "Algorithms for complex systems in the life sciences". Doctoral thesis, Politecnico di Torino, 2021. http://hdl.handle.net/11583/2910082.

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Zhang, Shile. "Integrative analysis of the metastatic neuroblastoma transcriptome". Thesis, 2016. https://hdl.handle.net/2144/14500.

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Neuroblastoma (NBL), the most common non-Central Nervous System (CNS) solid tumor of childhood, characteristically displays heterogeneous clinical presentation and biological behavior. Previous work has studied the genetic basis of the disease and revealed a low somatic mutation burden. In order to identify novel therapeutic targets and better understand the biology of high-risk NBLs, I investigated whole transcriptome profiles of two cohorts of metastatic NBLs using RNA sequencing. First, I studied changes in splicing pattern in a cohort of 29 patients. V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma Derived Homolog (MYCN) amplified NBLs showed a distinct splicing pattern affecting multiple cancer hallmarks. Six splicing factors have altered expression patterns in MYCN-amplified tumors and cell lines, and binding motifs for these factors were significantly enriched in differentially-spliced genes. ChIP-seq analysis showed direct binding of MYCN to promoter regions of splicing factors PTBP1 and HNRNPA1, demonstrating that MYCN regulates splicing by directly regulating expression of key splicing factors. Furthermore, high expression of PTBP1 and HNRNPA1 was significantly associated with poor overall survival of stage 4 NBL patients (p≤0.05). Knocking down PTBP1, HNRNPA1 and their downstream target PKM2, a pro-tumor-growth isoform, resulted in repression of NBL cell growth. Second, I used whole transcriptome sequencing in a cohort of 150 patients to assess expressed mutations, fusion genes, and gene expression including long non-coding genes to provide clinically-relevant classification and to offer insights into NBL tumor biology. Twenty-four genes including ALK, ATRX and MYCN were recurrently mutated in NBL transcriptomes. In-frame FOXR1 fusions were detected in 4 samples, including 3 cases or 14% of stage 4S NBLs. Unsupervised gene expression analysis revealed four molecular subgroups. MYCN and tumor microenvironment were the primary discriminating signatures in these molecular subgroups. Fifty-eight percent of MYCN-not-amplified samples showed high MYCN signatures, which were potentially contributed by various genomic events such as MYCN activating mutations and FOXR1 fusions. High MYCN signature was significantly associated with poor overall survival in MYCN-not-amplified tumors (p=0.0017). In addition, the tumor microenvironment including stromal and immune cell infiltration significantly contributed to the NBL transcriptional landscape and tumor progression.

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Buckberry, Sam. "An integrative analysis of the human placental transcriptome". Thesis, 2015. http://hdl.handle.net/2440/119553.

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Pregnancy outcome is inextricably linked to placental development, which is strictly regulated both temporally and spatially by mechanisms that are only partially understood. Although the placenta is absolutely indispensable for fetal development in utero, it remains the least understood human tissue. Although the placenta is a shared organ between the mother and fetus, it is of embryonic origin, and therefore its development is largely regulated by the fetal genome. This overall goal of this research was to investigate three key aspects of human placental gene regulation: (1) The effect of genomic imprinting on gene regulation, (2) the differences in placental gene expression between the sexes, and (3) the co-expression relationships that exist between genes on a transcriptome scale. Firstly, this research identified a window of epigenetic imprinting plasticity for the long non-coding RNA H19, which is heavily implicated in placental development and function. These results suggested that variation in H19 imprinting may contribute to early programming of placental phenotype and highlighted the need for quantitative and robust methodologies to further elucidate the role of imprinted genes in normal and pathological placental development. Secondly, by conducting a transcriptome-scale meta-analysis of sex-biased gene expression, this research revealed that 140 genes are differentially expressed between male and female placentae. A majority of these genes are autosomal, many of which are involved in high-level regulatory processes such as gene transcription, cell growth and proliferation and hormonal function. Of particular interest, all genes in the LHB-CGB cluster were expressed more highly in female placentas, which includes genes involved in placental development, the maintenance of pregnancy and maternal immune tolerance of the conceptus. These results demonstrated that sex-biased gene expression in the normal human placenta occurs across the genome and includes genes that are central to growth, development and the maintenance of pregnancy. Thirdly, by undertaking a comprehensive analysis of human placental gene co-expression using RNA sequencing and the integration of five human and one mouse transcriptome dataset, this research identified clusters of correlated genes, whose patterns of co-expression are highly preserved across human gestation and between human and mouse, subsequently revealing highly conserved molecular networks involved in placental development. Furthermore, by reducing the complexity of the placental transcriptome by summarizing co-expressed genes, this work identified a group of co-expressed genes implicated in preeclampsia and also outlines a novel method for identifying for non-invasive biomarkers of placental development. In summary, each aspect of this PhD research has provided new insights into how gene expression is regulated in the human placenta and has revealed previously unappreciated aspects of the placental transcriptional landscape.
Thesis (Ph.D.) (Research by Publication) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2015.

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Kusko, Rebecca. "Integrative transcriptomics in smoking related lung diseases". Thesis, 2015. https://hdl.handle.net/2144/15452.

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Chronic lung diseases including Chronic Obstructive Pulmonary Disease (COPD), Idiopathic Pulmonary Fibrosis (IPF) and lung cancer are major causes of morbidity and mortality in the United States due to high incidence and limited therapeutic options. In order to address this critical issue, I have leveraged RNA sequencing and integrative genomics to define disease-associated transcriptomic changes which could be potentially targeted to lead to new therapeutics. We sequenced the lung transcriptome of subjects with IPF (n=19), emphysema (n=19, a subtype of COPD), or neither (n=20). The expression levels of 1770 genes differed between IPF and control lung, and 220 genes differed between emphysema and control lung (p<0.001). Upregulated genes in both emphysema and IPF were enriched for the p53/hypoxia pathway. These results were validated by immunohistochemistry of select p53/hypoxia proteins and by GSEA analysis of independent expression microarray experiments. To identify regulatory events, I constructed an integrative miRNA target prediction and anticorrelation miRNA-mRNA network, which highlighted several miRNA whose expression levels were the opposite of genes differentially expressed in both IPF and emphysema. MiR-96 was a highly connected hub in this network and was subsequently overexpressed in cell lines to validate several potential regulatory connections. Building upon these successful experiments, I next sought to define gene expression changes and the miRNA-mRNA regulatory network in never smoker lung cancer. Large and small RNA was sequenced from matched lung adenocarcinoma tumor and adjacent normal lung tissue obtained from 22 subjects (8 never, 14 current and former smokers). I identified 120 genes whose expression was modified uniquely in never smoker lung tumors. Using a repository of gene-expression profiles associated with small bioactive molecules, several compounds which counter the never smoker tumor signature were identified in silico. Leveraging differential expression information, I again constructed an mRNA-miRNA regulatory network, and subsequently identified a potential never smoker oncomir has-mir-424 and its transcription factor target FOXP2. In this thesis, I have identified genes, pathways and the miRNA-mRNA regulatory network that is altered in COPD, IPF, and lung adenocarcinoma among never smokers. My findings may ultimately lead to improved treatment options by identifying targetable pathways, regulators, and therapeutic drug candidates.
2017-02-01T00:00:00Z

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Lu, Tzu-Pin, i 盧子彬. "Integrative Bioinformatics Approaches for Dynamic Time Series and Steady State Transcriptome Microarray Data". Thesis, 2011. http://ndltd.ncl.edu.tw/handle/49152827579496024539.

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博士
國立臺灣大學
生醫電子與資訊學研究所
99
Microarray technology has been widely utilized in biological and medical researches in the past two decades. The high-throughput feature facilitates the exploration of dysregulated cellular functions driven by experimental manipulations and identification of potential candidate genes for further validations. However, dealing with those massive data poses an exciting challenge in how to perform an efficient and accurate analysis. To address this issue, various statistical algorithms and mathematical models have been developed. In this dissertation, four bioinformatics approaches were presented and applied on two microarray datasets, three human lymphoblastoid cell lines exposed to radiation treatments and non-smoking female lung cancer patients in Taiwan. The first approach was a dynamic time series analysis, which explored the radiation-induced effects between higher and lower doses in the cells with different p53 status. Template-based clustering and tight clustering were performed to identify differentially expressed genes, and the results exhibited distinct signaling pathways in the three cell lines after 10Gy and iso-survival radiation exposures. After 10Gy radiation treatments, the p53 signaling pathway was triggered in TK6, whereas the NFkB signaling pathway was activated in WTK1 without functional p53 protein. Alternatively, irradiation with iso-survival doses induced down-regulations of many E2F4-related genes in all cell lines in spite of p53 status, which indicated that the E2F4 signaling pathway might serve as important regulators in response to lower dose radiation. The second approach investigated the gene expression profiles of non-smoking female lung cancer patients in Taiwan. This data set was composed of 60 pairs of tumor and adjacent normal tissue specimens. There were 687 differentially expressed genes in tumor tissue identified by paired t-test and significantly enriched in the pathway of axon guidance signaling. The varying patterns were highly similar to two public lung cancer datasets with both tumor and normal tissues from the same individual, which strengthened that these dysregulated genes were involved in lung tumorigenesis. Among them, the downregulation of SEMA5A in tumor tissue, both at the transcriptional and translational levels, was associated with poor survival outcomes. The results suggested that SEMA5A might be used as a novel biomarker for non-smoking female lung cancer patients. In the third approach, concurrent analyses of gene expression and copy number variations (CNVs) were performed in 42 pairs of non-smoking lung adenocarcinoma women. The results revealed the genomic landscape of recurrent copy number variated regions and 475 differentially expressed genes associated with CNVs. Among these CNV-driven genes, two important functions, survival regulation via AKT signaling and cytoskeleton reorganization, were significantly enriched. Survival analyses based on these enriched pathways demonstrated effective predictions in three independent microarray datasets, which suggested that those identified genes/pathways with concordant changes in both gene expression and CNV might be used as prognostic biomarkers for lung tumorigenesis. In the fourth approach, a comprehensive analysis was conducted in 32 pairs of non-smoking female lung adenocarcinoma patients to investigate SNPs, CNVs, methylation alterations, and gene expressions simultaneously. Associated co-varying patterns were observed between genetic modifications and transcriptional dysregulations. Three statistical approaches identified 617 SNP alleles related to CNVs or methylation alterations, and among them, Kruskal-Wallis test indicated 13 SNPs with downstream gene expression changes. Therefore, these SNPs with concordant changes in both DNA and RNA levels deserve more research efforts to elucidate their roles in lung cancer. In conclusion, these four bioinformatics approaches were effective in addressing biomedical issues and the results are confirmable in external datasets or biological experiments.

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GANGWAR, PAWAN SINGH. "INTEGRATIVE TRANSCRIPTOME DATA ANALYSIS REVEALS PSORIASIS SIGNATURE GENES AND ITS POTENTIAL ROLE IN DRUG REPURPOSING". Thesis, 2020. http://dspace.dtu.ac.in:8080/jspui/handle/repository/18059.

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Expression profiling of gene transcripts had been applied in biomedical researches successfully for over a decade. Psoriasis being a chronic inflammatory skin disorder have complex pathological features and unmet pharmacological demands. Therefore, a number of research studies have identified the genes which are differentially expressed in psoriasis skin as compared to the control or normal skin. Although, there is a considerable variance in the differentially expressed gene (DEG) list as reported by several research groups and the precise cause of psoriasis occurrence is still not understood entirely. In this study, the gene expression data from three different microarray studies, consisting of 117 samples in total and more than 1,35,000 transcripts, was analysed with the help of a ranking based approach. Subsequently, the 66 psoriatic gene expression signatures identified in total, were consistently showing dysregulation across the three studies. Furthermore, functional annotation of the identified genes implicated their role in skin development, epidermal development, keratinocyte differentiation, inflammation, immune response, and antimicrobial humoral response. By using a bioinformatics approach, skin development and keratinocyte differentiation pathway were identified as most over represented pathways among 66 signature genes. The main role of keratinocytes is in barrier function due to their presence in the epidermis. An enhanced understanding of keratinocytes function in psoriasis will prove to be important in developing novel barrier therapies for the disease. Finally, a framework is presented which identifies potential drug repositioning opportunities utilising a systemic data-driven approach which helps to discover association amongst genes, diseases and drugs. Such mechanisms facilitated potential drug repurposing for psoriasis by identifying and suggesting new indications of existing drugs.

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Mutwil, Marek [Verfasser]. "Integrative transcriptomic approaches to analyzing plant co-expression networks / Marek Mutwil". 2010. http://d-nb.info/1014229200/34.

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Israel, Jennifer Wygoda. "Sea Urchin Body Plan Development and Evolution: An Integrative Transcriptomic Approach". Diss., 2015. http://hdl.handle.net/10161/11327.

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My dissertation work integrates comparative transcriptomics and functional analyses to investigate gene expression changes underlying two significant aspects of sea urchin evolution and development: the dramatic developmental changes associated with an ecologically significant shift in life history strategy and the development of the unusual radial body plan of adult sea urchins.

In Chapter 2, I investigate evolutionary changes in gene expression underlying the switch from feeding (planktotrophic) to nonfeeding (lecithotrophic) development in sea urchins. In order to identify these changes, I used Illumina RNA-seq to measure expression dynamics across 7 developmental stages in three sea urchin species: the lecithotroph Heliocidaris erythrogramma, the closely related planktotroph Heliocidaris tuberculata, and an outgroup planktotroph Lytechinus variegatus. My analyses draw on a well-characterized developmental gene regulatory network (GRN) in sea urchins to understand how the ancestral planktotrophic developmental program was altered during the evolution of lecithotrophic development. My results suggest that changes in gene expression profiles occurred more frequently across the transcriptome during the evolution of lecithotrophy than during the persistence of planktotrophy. These changes were even more pronounced within the GRN than across the transcriptome as a whole, and occurred in each network territory (skeletogenic, endomesoderm and ectoderm). I found evidence for both conservation and divergence of regulatory interactions in the network, as well as significant changes in the expression of genes with known roles in larval skeletogenesis, which is dramatically altered in lecithotrophs. I further explored network dynamics between species using coexpression analyses, which allowed me to identify novel players likely involved in sea urchin neurogenesis and endoderm patterning.

In Chapter 3, I investigate developmental changes in gene expression underlying radial body plan development and metamorphosis in H. erythrogramma. Using Illumina RNA-seq, I measured gene expression profiles across larval, metamorphic, and post-metamorphic life cycle phases. My results present a high-resolution view of gene expression dynamics during the complex transition from pre- to post-metamorphic development and suggest that distinct sets of regulatory and effector proteins are used during different life history phases.

Collectively, my investigations provide an important foundation for future, empirical studies to investigate the functional role of gene expression change in the evolution of developmental differences between species and also for the generation of the unusual radial body plan of sea urchins.

Dissertation

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YE, ZONG HAN, i 葉宗翰. "Integration of cancer cell secretome and transcriptome for biomarker discovery of bladder cancer". Thesis, 2012. http://ndltd.ncl.edu.tw/handle/45711497032727101136.

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碩士
長庚大學
生物醫學研究所
100
Bladder cancer is the second in incidence and mortality cancer of the genitourinary system. Cystoscopy is the standard protocol in diagnosing bladder cancer. However, this procedure is invasive and expensive in clinical. Therefore, a non-invasive method for detection of bladder cancer is required. To date, several urine-based markers for bladder cancer have been identified and investigated, but none of them have shown sufficient sensitivity and specificity. Thus, discovery of novel bladder cancer biomarker is important. In the study, we analyzed the secretome of five bladder cancer cell lines, U1, U4, 5637, BFTC905 and TSGH8301, by the LC-MS/MS approach. 38 proteins were selected as biomarker candidates via the comparative analysis of secretomes between bladder cancer and nine other types of cancer cell lines, and urine exosome proteome. We also selected four potential marker candidates via analysis of mRNA expression profiles from Oncomine database. Immunohistochemical and ELISA analyses revealed an elevated expression of a candidate protein in bladder cancer tissues and urine specimens using adjacent non-cancerous tissue and hernia urine as controls.

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LE, PERA LOREDANA. "Unraveling the complexity of the human transcriptome: analysis and integration of high-throughput data". Doctoral thesis, 2013. http://hdl.handle.net/11573/918415.

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BACKGROUND: An undoubted outcome of the last decade genomics research is the evidence of our lack of knowledge about the complexity of the human transcriptome. Researchers found, at first, that there were far fewer genes than expected (<25,000 genes coding for proteins), only to discover later that there were far more non protein-coding transcripts than expected (~30,000). Surprisingly, the transcriptome diversity is also due to a wider occurrence of alternative splicing than previously suspected. It is now clear that about 95% of the human multi-exon genes undergo alternative splicing events. At the same time, a number of studies from others and from our group have shown that a significant fraction of all generated transcripts, or isoforms, are unlikely to be translated into functional protein products. Although the emerging complex picture of transcriptomes is exciting, and genome-scale information is freely accessible from public repositories, there is still to develop approaches that permit a comprehensive characterization and efficient validation of the data. In this context, the progress and contributions of next-generation sequencing techniques have been crucial. By generating high-throughput experimental data and performing bioinformatics processing analysis, it is potentially possible to investigate and compare both protein- and non protein-coding element behaviours in specific biological and biomedical problems. Both the large-scale data generated from international consortium projects and the high-throughput experimental data produced in specific experiments challenge us to translate this massive information into meaningful biological insights. AIM: My thesis focuses on the identification and characterization of functional protein-coding and non-protein-coding products of the human transcriptome, by integrating a combination of various computational methods and biological data. The first part of the study aims at defining a strategy to assess the protein-coding potential of alternative splicing products, by analyzing all genome-scale transcripts available in public repositories. Sequence and structure features of known proteins are investigated and combined using bioinformatics approaches. This study attempts to assess the ability of different criteria to detect most of the actually translated isoforms and can be of great help in estimating the real size of the human proteome (an information that is still missing). The second part of the study aims at detecting functional protein-coding and non-protein-coding transcripts, analyzing high-throughput RNA-sequencing expression data in specific biomedical problems. The analysis investigates mRNA, taking into account all the possible isoforms, and microRNA expression profiles. In order to elucidate and assess a putative regulatory key role of microRNAs in the biological processes under study, a procedure is developed to identify enriched microRNA/mRNA-target associations. RESULTS: The first analysis was focused on human protein-coding genes having at least one protein isoform unequivocally identified by mass-spectrometry peptide data (Positive dataset) and at least one other isoform with no evidence of translation (Unknown dataset). A number of sequence and structural features of typical functional proteins were used to compare the properties of the two isoform datasets. We found out that Positive isoforms are predicted to be structurally more plausible than Unknown isoforms; functional domains are more often truncated in Unknown isoforms than in Positive ones; functional features such as active sites are rarely disrupted in Positive isoforms. Combining the presence of non-truncated functional domains with an assessment of the plausibility of the modelled structure, the estimated percentage of non-plausible protein-coding transcripts is about 45% of the Unknown isoforms. To capture further differences between functional and non functional transcripts, the following features were also investigated: selection pressure, conservation among multiple species and stringent comparison between human and mouse. The second analysis aimed at detecting all the putative functional transcripts involved in biological processes investigated by RNA-sequencing technique. Specialized bioinformatics procedures were set up to analyze both mRNA and microRNA expression profiles and were applied to specific biomedical problems in collaboration with experimental groups. Additionally, integrating also microRNA/target-gene prediction algorithms, the method allows the automatic identification of differentially expressed microRNAs predicted to bind mRNAs that are inversely-regulated in the same experiment. This combined analysis of microRNA and target-mRNA expression data is useful to isolate putative regulatory circuits involved in the investigated biological processes.

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Huang, Fei Fan, i 黃飛凡. "Integration of secretome and transcriptome for biomarker discovery and clinical application of renal cell carcinoma". Thesis, 2017. http://ndltd.ncl.edu.tw/handle/qmk8vg.

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碩士
長庚大學
生物醫學研究所
105
Renal cell carcinoma (RCC) is difficult to diagnose at the early stage. Recently. Studies of cell secretome are greatly increasing because of the improvement in proteomic quantitation, mass spectrometry and the secretome database. The studies of cancer cell secretome can help us to find biomarker candidates. The experimental design of this project is comparing the cell lysate and secretomes using cell lysate proteins as well as secretory proteins in conditioned media from cell lines of normal kidney cells (HK-2) and kidney cancer cell lines (786-O、A-498、BFTC 909), respectively. The four samples of cell lysate and secretome were labeled with isobaric reagent of 4-plexed isobaric tags for relative and absolute quantitation (iTRAQ) reagents. The iTRAQ-labeled peptides were identified and quantified by LC/MS/MS, and the raw data were processed by PD software. According to the preliminary data, we identified a total of 5543 and 2310 proteins in cell lysate and secretome, respectively. 456 and 183 proteins were up-regulate (>mean+1SD) in cell lysate and secretome, respectively. 77 proteins were up-regulate in both lysate and secretome. We integrated the proteomic changes with transcriptomic cancer microarray database, ONCOMINE. Among the 77 proteins, 7 proteins that were up-expressed in clear cell renal cell carcinoma datasets were selected as biomarker candidates for RCC biomarker verification. These 7 proteins will be quantified in cell lysates, conditional medium, and individual samples of clinical urine and tissue of RCC patients to evaluate the clinical performance using ROC curves. The results will provide a complete RCC proteomic profiling of cell lysate and secretome as well as potential biomarker candidates for developing non-invasive biomarkers of RCC.

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Sitte, Maren. "Network Based Integration of Proteomic and Transcriptomic Data: Study of BCR and WNT11 Signaling Pathways in Cancer Cells". Doctoral thesis, 2020. http://hdl.handle.net/21.11130/00-1735-0000-0005-1397-B.

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Li, Zhengcao. "Integrating Omics Data into Genomic Prediction". Doctoral thesis, 2019. http://hdl.handle.net/21.11130/00-1735-0000-0003-C178-C.

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"Thermal adaptation of the marine snail Echinolittorina malaccana: an integrative comparative transcriptomic and population genetic study". 2014. http://repository.lib.cuhk.edu.hk/en/item/cuhk-1292099.

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Wang, Wei.
Thesis Ph.D. Chinese University of Hong Kong 2014.
Includes bibliographical references (leaves 118-139).
Abstracts also in Chinese.
Title from PDF title page (viewed on 21, December, 2016).

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Wachter, Astrid. "Data Integration of High-Throughput Proteomic and Transcriptomic Data based on Public Database Knowledge". Doctoral thesis, 2017. http://hdl.handle.net/11858/00-1735-0000-0023-3E4B-9.

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Bewerunge, Peter [Verfasser]. "Integrative data mining and meta analysis of disease-specific large-scale genomic, transcriptomic and proteomic data / presented by Peter Bewerunge". 2009. http://d-nb.info/997856645/34.

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Ribeiro, Ilda Patrícia Tavares da Silva. "Head and Neck Squamous Cell Carcinoma: integrating genomic, epigenetic and transcriptomic data - from bench to clinical applications". Doctoral thesis, 2017. http://hdl.handle.net/10316/79613.

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Tese de doutoramento do Programa Interuniversitário de Doutoramento em Envelhecimento e Doenças Crónicas, apresentada à Faculdade de Medicina da Universidade de Coimbra
Head and neck squamous cell carcinoma (HNSCC) is an emergent health problem worldwide. These tumors present heterogeneity at phenotypic, aetiological, biological and clinical level. In developed countries, smoking and alcohol are implicated in the increase of HNSCC cases, and human papillomavirus is an important risk factor, especially in the rise of oropharyngeal tumors without smoke and alcohol habits. A significant percentage of HNSCC patients develop loco-regional and distant recurrences. Even with progresses in surgery, radiation and chemotherapy, approximately half of all patients die of the disease. Risk stratification for HNSCC is essencial in order to decrease mortality and improve quality of life of the patients. The great HNSCC heterogeneity makes difficult to understand the molecular carcinogenesis process as well as to develop early detection and therapeutic strategies for these tumors. Nowadays, the majority of genome-wide molecular profiling studies of HNSCC are limited to single approaches, which hampers the identification of accurate and robust biomarkers of early diagnosis and prognosis. Indeed, there is a lack of proven biomarkers for predicting clinical outcomes and response to treatment. The present work aimed to perform a molecular characterization of HNSCC in order to predict recurrence/metastasis development and signaling pathways associated to targeted therapy and resistance to conventional drugs through the identification of different molecular groups with apparently different survival profiles using genomic, epigenetic and transcriptomic approaches. We analyzed the same HNSCC patients through different molecular technologies, being the identified biomarkers and molecular signatures validated with TCGA (The Cancer Genome Atlas) data. First, we performed a direct genetic and epigenetic characterization of HNSCC patients, using specific Multiplex Ligation-dependent Probe Amplification (MLPA) and Methylation-Specific MLPA (MS-MLPA) probe panels. We reported different genetic signatures related to tumor stage and anatomic site as well as tobacco use. Additionally, specific genomic and epigenetic signatures associated to patients' risk of recurrence/metastasis development after treatment of primary tumor and also to survival were identified. The genetic analysis of non-tumor samples (from surgical margins) revealed some imbalances similar to those identified in the tumor samples, which reinforce the importance of molecularly analyze the high-risk patients even before the visible morphological changes and also the suspicious lesions in order to early diagnose these tumors and their recurrences. Secondly, we moved forward to a high-throughput genomic and transcriptomic approaches and we identified molecular signatures with capability to predict the recurrent/metastatic disease development and clinical outcome. In these studies using either direct probe panels or genome-wide approaches we identified the most common chromosomal regions with imbalances and altered genes. As expected, whole-genome techniques revealed new chromosomal regions and genes that seem to have a role in HNSCC development and behavior. Overall, through these comprehensive genomic, epigenetic and transcriptomic characterization we identified biomarkers and molecular signatures of prognosis and survival, which open the door for personalized medicine in HNSCC patients. Finally, we applied these genomic and epigenetic technologies to perform a molecular characterization of four paradigmatic HNSCC patients in order to prove the benefit of these molecular knowledgement to the clinical management of the HNSCC patients. Several chromosomal regions and genes related to radiation and/or chemotherapy resistance and to patients' prognosis and survival were identified, which could help and guide the type or intensify of treatment modalities. Moreover, molecular characterization of commercial HNSCC cell lines and primary cell cultures established from these patients was conducted, which revealed the ploidy and the complex structural chromosomal rearrangements of HNSCC tumors. This comprehensive characterization enables cell models for further studies both in radiation and pharmacogenomics fields, as well as to understand the molecular mechanisms of HNSCC development and progression. With this work we performed a robust molecular characterization of HNSCC, using different omic approaches in the same tumor samples, which allowed the identification of new prognostic biomarkers and molecular signatures with potential to be translated to clinical practice.
O carcinoma epidermóide da cabeça e pescoço (CECP) é um problema emergente de saúde em todo o mundo. Estes tumores são heterogéneos a nível fenótipico, etiológico, biológico e clínico. Nos países desenvolvidos, o tabaco e o álcool estão implicados no aumento do número de casos de CECP e o papiloma vírus humano é um fator de risco importante para o aumento dos tumores da orofaringe não relacionados com hábitos tabágicos e de álcool. Uma percentagem significativa de doentes com CECP desenvolve recidivas loco-regionais e à distância. Mesmo com os progressos na cirurgia, radioterapia e quimioterapia, cerca de metade de todos os doentes morre devido ao CECP. A estratificação do risco de CECP é essencial de forma a contribuir para a diminuição da mortalidade e melhoria da qualidade de vida destes doentes. A heterogeneidade do CECP dificulta por um lado a compreensão dos processos moleculares da carcinogénese e por outro lado o desenvolvimento de estratégias de deteção precoce e de terapêutica. Atualmente, a maioria dos estudos moleculares de grande escala são restritos, o que dificulta a identificação robusta e precisa de biomarcadores de diagnóstico e prognóstico. De facto, há falta de biomarcadores para predizer o desenlace clínico e resposta ao tratamento. O presente trabalho teve como objetivo caraterizar molecularmente o CECP de forma a prever o desenvolvimento de recidivas/metástases e a identificação de vias de sinalização associadas a terapias alvo e resistência às terapias convencionais, através da identificação de diferentes grupos moleculares com diferentes sobrevivências, usando abordagens de genómica, epigenética e transcriptómica. Neste estudo, analisámos os mesmos doentes com CECP usando diferentes tecnologias moleculares, tendo validado os biomarcadores e assinaturas moleculares identificados usando dados do portal TCGA (The Cancer Genome Atlas). Em primeiro lugar, realizámos uma caraterização genética e epigenética do CECP direcionada, utilizando painéis de sondas específicos de Multiplex Ligation-dependent Probe Amplification (MLPA) e Methylation-Specific MLPA (MS-MLPA). Identificaram-se diferentes assinaturas genéticas relacionadas com o estadio do tumor e as localizações anatómicas, bem como com o consumo de tabaco. Adicionalmente, uma assinatura genética e epigenética associada ao risco dos doentes desenvolverem recidivas/metástases após o tratamento do tumor primário e também associada à sobrevivência, foi identificada. A análise genética das amostras não tumorais (provenientes das margens cirúrgicas) revelou alguns desequilíbrios similares aos identificados nas amostras tumorais, o que reforça a importância de analisar molecularmente os doentes de elevado risco mesmo antes de qualquer alteração morfológica visível e também das lesões suspeitas, de forma a diagnosticar precocemente estes tumores e as suas recidivas. Na segunda parte do estudo utilizámos abordagens genómicas e transcriptómicas de larga escala e, identificámos assinaturas moleculares capazes de prever o desenvolvimento de recidivas/metástases e evolução clínica dos doentes. Estes estudos, usando quer painéis de sondas direcionados quer abordagens de todo o genoma, permitiram identificar as regiões cromossómicas e genes mais comummente alterados. As técnicas de análise de todo o genoma revelaram novas regiões cromossómicas e genes que parecem desempenhar um papel no desenvolvimento e evolução clínica do CECP. No geral, através desta caraterização genómica, epigenética e trasncriptómica, identificámos biomarcadores e assinaturas moleculares de prognóstico e sobrevivência, o que abre novas portas para a medicina personalizada no CECP. Finalmente, utilizámos estas tecnologias de genómica e epigenética para caraterizar quatro doentes paradigmáticos com CECP de forma a provar o benefício deste conhecimento molecular na conduta clínica. Várias regiões cromossómicas e genes relacionados com a resistência à radiação, quimioterapia, prognóstico e sobrevivência foram identificados, o que poderia ajudar na escolha do tipo e intensidade das modalidades de tratamento. Adicionalmente, foi realizada a caraterização molecular de linhas comerciais de CECP e de culturas primárias estabelecidas a partir destes doentes de CECP, o que revelou a ploidia e rearranjos estruturais complexos destes tumores, garantindo modelos celulares para futuros estudos no campo da radiação e farmacogenómica e ainda para uma melhor compreensão dos mecanismos moleculares de desenvolvimento e progressão do CECP. Este trabalho permitiu, de uma forma robusta, caracterizar molecularmente o CECP, usando diferentes abordagens ómicas nas mesmas amostras tumorais, ajudando assim a identificar novos biomarcadores de prognóstico e assinaturas moleculares com potencial translação à clínica.

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