Academic literature on the topic 'Genome conformation'
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Journal articles on the topic "Genome conformation"
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Wang, Yanbo, John Mallon, Haobo Wang, et al. "Real-time observation of Cas9 postcatalytic domain motions." Proceedings of the National Academy of Sciences 118, no. 2 (2020): e2010650118. http://dx.doi.org/10.1073/pnas.2010650118.
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CRISPR-Cas9 fromStreptococcus pyogenesis an RNA-guided DNA endonuclease, which has become the most popular genome editing tool. Coordinated domain motions of Cas9 prior to DNA cleavage have been extensively characterized but our understanding of Cas9 conformations postcatalysis is limited. Because Cas9 can remain stably bound to the cleaved DNA for hours, its postcatalytic conformation may influence genome editing mechanisms. Here, we use single-molecule fluorescence resonance energy transfer to characterize the HNH domain motions of Cas9 that are coupled with cleavage activity of the target strand (TS) or nontarget strand (NTS) of DNA substrate. We reveal an NTS-cleavage-competent conformation following the HNH domain conformational activation. The 3′ flap generated by NTS cleavage can be rapidly digested by a 3′ to 5′ single-stranded DNA-specific exonuclease, indicating Cas9 exposes the 3′ flap for potential interaction with the DNA repair machinery. We find evidence that the HNH domain is highly flexible post-TS cleavage, explaining a recent observation that the HNH domain was not visible in a postcatalytic cryo-EM structure. Our results illuminate previously unappreciated regulatory roles of DNA cleavage activity on Cas9’s conformation and suggest possible biotechnological applications.
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Fujishiro, Shin, Naoko Tokuda, and Masaki Sasai. "2P267 Computational chromosome conformation sampling of human diploid genome(21B. Genome biology:Genome structure,Poster)." Seibutsu Butsuri 54, supplement1-2 (2014): S239. http://dx.doi.org/10.2142/biophys.54.s239_3.
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Sanford, Thomas J., Harriet V. Mears, Teodoro Fajardo, Nicolas Locker, and Trevor R. Sweeney. "Circularization of flavivirus genomic RNA inhibits de novo translation initiation." Nucleic Acids Research 47, no. 18 (2019): 9789–802. http://dx.doi.org/10.1093/nar/gkz686.
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Abstract Members of the Flaviviridae family, including dengue virus (DENV) and yellow fever virus, cause serious disease in humans, whilst maternal infection with Zika virus (ZIKV) can induce microcephaly in newborns. Following infection, flaviviral RNA genomes are translated to produce the viral replication machinery but must then serve as a template for the transcription of new genomes. However, the ribosome and viral polymerase proceed in opposite directions along the RNA, risking collisions and abortive replication. Whilst generally linear, flavivirus genomes can adopt a circular conformation facilitated by long-range RNA–RNA interactions, shown to be essential for replication. Using an in vitro reconstitution approach, we demonstrate that circularization inhibits de novo translation initiation on ZIKV and DENV RNA, whilst the linear conformation is translation-competent. Our results provide a mechanism to clear the viral RNA of ribosomes in order to promote efficient replication and, therefore, define opposing roles for linear and circular conformations of the flavivirus genome.
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Shepherd, Jeremiah J., Lingxi Zhou, William Arndt, Yan Zhang, W. Jim Zheng, and Jijun Tang. "Exploring genomes with a game engine." Faraday Discuss. 169 (2014): 443–53. http://dx.doi.org/10.1039/c3fd00152k.
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More and more evidence indicates that the 3D conformation of eukaryotic genomes is a critical part of genome function. However, due to the lack of accurate and reliable 3D genome structural data, this information is largely ignored and most of these studies have to use information systems that view the DNA in a linear structure. Visualizing genomes in real time 3D can give researchers more insight, but this is fraught with hardware limitations since each element contains vast amounts of information that cannot be processed on the fly. Using a game engine and sophisticated video game visualization techniques enables us to construct a multi-platform real-time 3D genome viewer. The game engine-based viewer achieves much better rendering speed and can handle much larger amounts of data compared to our previous implementation using OpenGL. Combining this viewer with 3D genome models from experimental data could provide unprecedented opportunities to gain insight into the conformation–function relationships of a genome.
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Brigham, Benjamin S., Jonathan P. Kitzrow, Joshua-Paolo C. Reyes, Karin Musier-Forsyth, and James B. Munro. "Intrinsic conformational dynamics of the HIV-1 genomic RNA 5′UTR." Proceedings of the National Academy of Sciences 116, no. 21 (2019): 10372–81. http://dx.doi.org/10.1073/pnas.1902271116.
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The highly conserved 5′ untranslated region (5′UTR) of the HIV-1 RNA genome is central to the regulation of virus replication. NMR and biochemical experiments support a model in which the 5′UTR can transition between at least two conformational states. In one state the genome remains a monomer, as the palindromic dimerization initiation site (DIS) is sequestered via base pairing to upstream sequences. In the second state, the DIS is exposed, and the genome is competent for kissing loop dimerization and packaging into assembling virions where an extended dimer is formed. According to this model the conformation of the 5′UTR determines the fate of the genome. In this work, the dynamics of this proposed conformational switch and the factors that regulate it were probed using multiple single-molecule and in-gel ensemble FRET assays. Our results show that the HIV-1 5′UTR intrinsically samples conformations that are stabilized by both viral and host factor binding. Annealing of tRNALys3, the primer for initiation of reverse transcription, can promote the kissing dimer but not the extended dimer. In contrast, HIV-1 nucleocapsid (NC) promotes formation of the extended dimer in both the absence and presence of tRNALys3. Our data are consistent with an ordered series of events that involves primer annealing, genome dimerization, and virion assembly.
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You, Chuihuai, Tianzhen Cui, Chang Zhang, Shoujian Zang, Yachun Su, and Youxiong Que. "Assembly of the Complete Mitochondrial Genome of Gelsemium elegans Revealed the Existence of Homologous Conformations Generated by a Repeat Mediated Recombination." International Journal of Molecular Sciences 24, no. 1 (2022): 527. http://dx.doi.org/10.3390/ijms24010527.
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Gelsemium elegans (G. elegans) is a Chinese medicinal plant with substantial economic and feeding values. There is a lack of detailed studies on the mitochondrial genome of G. elegans. In this study, the mitochondrial genome of G. elegans was sequenced and assembled, and its substructure was investigated. The mitochondrial genome of G. elegans is represented by two circular chromosomes of 406,009 bp in length with 33 annotated protein-coding genes, 15 tRNA genes, and three rRNA genes. We detected 145 pairs of repeats and found that four pairs of repeats could mediate the homologous recombination into one major conformation and five minor conformations, and the presence of conformations was verified by PCR amplification and Sanger sequencing. A total of 124 SSRs were identified in the G. elegans mitochondrial genome. The homologous segments between the chloroplast and mitochondrial genomes accounted for 5.85% of the mitochondrial genome. We also predicted 477 RNA potential editing sites and found that the nad4 gene was edited 38 times, which was the most frequent occurrence. Taken together, the mitochondrial genome of G. elegans was assembled and annotated. We gained a more comprehensive understanding on the genome of this medicinal plant, which is vital for its effective utilization and genetic improvement, especially for cytoplasmic male sterility breeding and evolution analysis in G. elegans.
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Gu, Bowen, Ruifan Sun, Xingqiang Fang, et al. "Genome-Wide Association Study of Body Conformation Traits by Whole Genome Sequencing in Dazu Black Goats." Animals 12, no. 5 (2022): 548. http://dx.doi.org/10.3390/ani12050548.
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Identifying associations between genetic markers and economic traits has practical benefits for the meat goat industry. To better understand the genomic regions and biological pathways contributing to body conformation traits of meat goats, a genome-wide association study was performed using Dazu black goats (DBGs), a Chinese indigenous goat breed. In particular, 150 DBGs were genotyped by whole-genome sequencing, and six body conformation traits, including body height (BH), body length (BL), cannon circumference (CC), chest depth (CD), chest width (CW), and heart girth (HG), were examined. In total, 53 potential SNPs were associated with these body conformation traits. A bioinformatics analysis was performed to evaluate the genes located close to the significant SNPs. Finally, 42 candidate genes (e.g., PSTPIP2, C7orf57, CCL19, FGF9, SGCG, FIGN, and SIPA1L) were identified as components of the genetic architecture underlying body conformation traits. Our results provide useful biological information for the improvement of growth performance and have practical applications for genomic selection in goats.
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Bentley, Kirsten, Jonathan P. Cook, Andrew K. Tuplin, and David J. Evans. "Structural and functional analysis of the roles of the HCV 5′ NCR miR122-dependent long-range association and SLVI in genome translation and replication." PeerJ 6 (November 6, 2018): e5870. http://dx.doi.org/10.7717/peerj.5870.
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The hepatitis C virus RNA genome possesses a variety of conserved structural elements, in both coding and non-coding regions, that are important for viral replication. These elements are known or predicted to modulate key life cycle events, such as translation and genome replication, some involving conformational changes induced by long-range RNA–RNA interactions. One such element is SLVI, a stem-loop (SL) structure located towards the 5′ end of the core protein-coding region. This element forms an alternative RNA–RNA interaction with complementary sequences in the 5′ untranslated regions that are independently involved in the binding of the cellular microRNA 122 (miR122). The switch between ‘open’ and ‘closed’ structures involving SLVI has previously been proposed to modulate translation, with lower translation efficiency associated with the ‘closed’ conformation. In the current study, we have used selective 2′-hydroxyl acylation analysed by primer extension to validate this RNA–RNA interaction in the absence and presence of miR122. We show that the long-range association (LRA) only forms in the absence of miR122, or otherwise requires the blocking of miR122 binding combined with substantial disruption of SLVI. Using site-directed mutations introduced to promote open or closed conformations of the LRA we demonstrate no correlation between the conformation and the translation phenotype. In addition, we observed no influence on virus replication compared to unmodified genomes. The presence of SLVI is well-documented to suppress translation, but these studies demonstrate that this is not due to its contribution to the LRA. We conclude that, although there are roles for SLVI in translation, the LRA is not a riboswitch regulating the translation and replication phenotypes of the virus.
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Tjong, Harianto, Wenyuan Li, Reza Kalhor, et al. "Population-based 3D genome structure analysis reveals driving forces in spatial genome organization." Proceedings of the National Academy of Sciences 113, no. 12 (2016): E1663—E1672. http://dx.doi.org/10.1073/pnas.1512577113.
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Conformation capture technologies (e.g., Hi-C) chart physical interactions between chromatin regions on a genome-wide scale. However, the structural variability of the genome between cells poses a great challenge to interpreting ensemble-averaged Hi-C data, particularly for long-range and interchromosomal interactions. Here, we present a probabilistic approach for deconvoluting Hi-C data into a model population of distinct diploid 3D genome structures, which facilitates the detection of chromatin interactions likely to co-occur in individual cells. Our approach incorporates the stochastic nature of chromosome conformations and allows a detailed analysis of alternative chromatin structure states. For example, we predict and experimentally confirm the presence of large centromere clusters with distinct chromosome compositions varying between individual cells. The stability of these clusters varies greatly with their chromosome identities. We show that these chromosome-specific clusters can play a key role in the overall chromosome positioning in the nucleus and stabilizing specific chromatin interactions. By explicitly considering genome structural variability, our population-based method provides an important tool for revealing novel insights into the key factors shaping the spatial genome organization.
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Bolovan-Fritts, Cynthia A., Edward S. Mocarski, and Jean A. Wiedeman. "Peripheral Blood CD14+ Cells From Healthy Subjects Carry a Circular Conformation of Latent Cytomegalovirus Genome." Blood 93, no. 1 (1999): 394–98. http://dx.doi.org/10.1182/blood.v93.1.394.
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Abstract The majority of the human population harbors latent cytomegalovirus. Although CD14+ peripheral blood mononuclear cells have been implicated as sites of latency, the conformation of the latent viral genome in these cells is unknown. In this study, the conformation of viral genomic DNA was assessed in CD14+ cells from healthy virus seropositive carriers using an electrophoretic separation on native agarose gels in combination with polymerase chain reaction detection. Here we show that the viral genome migrates as a circular plasmid with a mobility equivalent to a circular 230-kb Shigella flexneri megaplasmid marker. Neither linear nor complex or integrated forms of the viral genome were detected. This report provides further evidence that the CD14+ cell population is an important site of viral latency in the naturally infected human host. Detection of the viral genome as a circular plasmid during latency suggests that this virus maintains its genome in a manner analogous to other herpesviruses where latent viral genome conformation has been studied.
Dissertations / Theses on the topic "Genome conformation"
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Nicoletti, Chiara. "Genome conformation and transcription regulation: methods and applications." Doctoral thesis, Università degli studi di Padova, 2017. http://hdl.handle.net/11577/3424943.
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The 3D organization of chromatin within the nucleus is crucial for genome functionality. This is true at multiple levels of resolution: on a large scale, with chromosomes occupying distinct volumes (chromosome territories), at the level of
individual chromatin fibers, organized in compartmentalized domains (as the Topologically Associating Domains, TADs), and down to the formation of short range chromatin interactions (as enhancer-promoter loops). The widespread adoption of high-throughput techniques derived from Chromosome Conformation Capture (3C) has been instrumental in advancing the knowledge of chromatin nuclear organization. In particular, Hi-C has the potential to achieve the most comprehensive characterization of chromatin 3D interactions, as in principle it can detect any pair of restriction fragments connected as a result of ligation by proximity. The analysis of the enormous amount of genomic data produced by Hi-C required the development of ad hoc algorithms and computational procedures. Despite the increasing number of available bioinformatics pipelines, no consensus on the optimal approach to analyze Hi-C data has been reached yet. Therefore, we quantitatively compared several Hi-C data analysis methods for the identification of multi-scale chromatin structures to highlight strengths and weaknesses of the various methods and propose application guidelines and good practices. Specifically, we compared different computational approaches (6 for the characterization of chromatin loops and 7 to identify TADs) using publicly available Hi-C datasets, comprising data from different species and cell lines, Hi-C protocol variations and data resolution. Additionally, the algorithms were tested on simulated Hi-C data to assess sensitivity and precision of each method. The tools differed in terms of implemented analysis steps and strategies adopted for alignment, filtering, normalization, and feature identification (global or local looping interactions calling and single-scale or multi-scale TAD discovery). Results of this comparison indicate that performances of the methods considerably vary, both in quantitative and qualitative terms, and that the tools need extensive optimization of the parameters in order to work properly. Despite, in general, TAD callers resulted riper than algorithms to call interactions, still most of them are characterized by crucial limitations, as for instance the inability to investigate how the 3D organization of chromatin structures
evolves over time (as e.g., during differentiation). Although the molecular mechanisms underlying TADs formation are still debated, it is evident that distinct interaction patterns can be observed within individual TADs. In particular, some domains appear to have a very compact structure, while others have a less uniform or weaker interaction frequency within the domain, while showing a strong interaction between the borders.
To address these limitations, I developed TAD-AH (TADs Advanced Hierarchy), a four-step sequential procedure coded in R, for the characterization of both static and dynamically changing chromatin domains. As a case study, I analyzed Hi-C data generated prior and post human fibroblasts (IMR90) trans-differentiation into skeletal muscle cells (myoblasts, and, when put in differentiation media, myotubes) by overexpression of muscle stem cells master regulator MyoD. I integrated Hi-C with epigenomic and transcriptomic data from the same conditions and confirmed that the identified genomic features are consistent with the biological scenario under scrutiny.<br>L’organizzazione tridimensionale della cromatina all’interno del nucleo è alla base della regolazione funzionale del genoma, sia a livello macroscopico, dove i cromosomi occupano spazi distinti (territori cromosomici), sia a livello di singole fibre, dove la cromatina si organizza in domini compartimentalizzati (Topologically Associating Domains, TADs), dentro i quali avviene la formazione di interazioni a corto raggio (come quelle che sussistono tra promotori e regioni regolatrici). Le tecniche denominate Chromosome Conformation Capture (3C) hanno permesso di investigare e caratterizzare i diversi livelli dell’organizzazione strutturale della cromatina all’interno del nucleo. In particolare, l’Hi-C, attraverso la combinazione del protocollo di 3C e del sequenziamento massivo, è in grado di restituire un’immagine completa dell’architettura della cromatina e dei contatti all’interno del genoma. Nonostante in questi ultimi anni siano stati resi disponibili diversi strumenti computazionali per l’analisi dei dati di Hi-C, non esiste tuttora un consenso su quale sia il metodo ottimale da usare. Una valutazione comparativa dei software per l'analisi dei dati Hi-C è quindi necessaria non solo per evidenziare i punti di forza e le debolezze dei vari metodi, ma anche per proporre linee guida utili all’utente medio. Per questo motivo ho applicato diversi approcci computazionali (6 per la caratterizzazione delle interazioni e 7 per identificare i TAD) a 6 set di dati pubblici di Hi-C, relativi a diverse specie e linee cellulari (H1-hESC, IMR90, linee cellulari linfoblastoidi ed embrioni di D. melanogaster), a differenti metodiche sperimentali (standard Hi-C, simplified Hi-C e In situ Hi-C) e analizzati a diverse risoluzioni. Inoltre, gli algoritmi sono stati applicati a dati simulati per determinare sensibilità e precisione di ogni metodo. I software differiscono sia per le fasi di analisi implementate sia per le strategie adottate in ciascun passaggio: l'allineamento della sequenza completa contro quello della sequenza “spezzata”, i filtri applicati, la normalizzazione implicita contro quella esplicita, l’arricchimento di interazione locale contro quello globale e l’individuazione di TAD ad uno o più livelli. I metodi variano molto a livello di prestazioni sia in termini quantitativi sia qualitativi, e richiedono di ottimizzare un’ampia gamma di parametri per funzionare correttamente. Nonostante, in generale, gli algoritmi per identificare i TAD si siano dimostrati più affidabili di quelli per trovare le interazioni, ci sono ancora dei limiti fondamentali nell’identificazione dei TAD, ad esempio nello studio dell’evoluzione di queste strutture nel tempo. Sebbene i meccanismi alla base della formazione dei TAD siano tuttora dibattuti, è innegabile che questi siano caratterizzati da pattern distintivi di interazione: in alcuni TAD possiamo osservare un segnale di interazione più omogeneo, mentre in altri l’interazione è più che altro evidente tra le regioni che lo delimitano. Per superare questi limiti, ho sviluppato un nuovo metodo per l’analisi dei TAD a partire da dati di Hi-C (TAD-AH), atto ad indagare un aspetto finora inesplorato dell'architettura del genoma: la quarta dimensione, ovvero come la struttura si evolve nel tempo in base a stimoli di varia natura (ad esempio durante il differenziamento). Per testare TAD-AH ho analizzato dati di Hi-C generati prima e dopo il trans-differenziamento di fibroblasti umani (IMR90) in cellule muscolari (mioblasti e miotubi) ad opera del principale regolatore delle cellule staminali muscolari, MYOD. L’integrazione dei dati di Hi-C con altri dati epigenomici e trascrittomici ha confermato che la caratterizzazione delle strutture identificate è coerente con lo scenario biologico in esame.
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Boulos, Rasha. "Human genome segmentation into structural domains : from chromatin conformation data to nuclear functions." Thesis, Lyon, École normale supérieure, 2015. http://www.theses.fr/2015ENSL1024/document.
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Le programme de réplication d’environ la moitié du génome des mammifères est caractérisé par des U/N-domaines de réplication de l’ordre du méga-base en taille. Ces domaines sont bordés par des origines de réplication maitresses (MaOris) correspondantes à des régions (~200 kb) de chromatine ouverte favorables à l’initiation précoce de la réplication et de la transcription. Grâce au développement récent de technologies à haut débit de capture de conformations des chromosomes (Hi-C), des matrices de fréquences de co-localisation 3D entre toutes les paires de loci sont désormais déterminées expérimentalement. Il est apparu que les U/N-domaines sont reliés à l’organisation du génome en unités structurelles. Dans cette thèse, nous avons effectué une analyse combinée de données de Hi-C de lignées cellulaires humaines et de profils de temps de réplication pour explorer davantage les relations structure/fonction dans le noyau. Cela nous a conduit à décrire de nouveaux domaines de réplication de grande tailles (>3 Mb) : les split-U-domaines aussi bordés par des MaOris; à démontrer que la vague de réplication initiée aux MaOris ne dépend que du temps pendant la phase S et de montrer que le repliement de la chromatine est compatible avec un modèle d’équilibre 3D pour les régions euchromatiniennes à réplication précoces et un modèle d’équilibre 2D pour les régions heterochromatiniennes à réplication tardives associées à la lamina nucléaire. En représentant les matrices de co-localisation issues du Hi-C en réseaux d’interactions structurelles et en déployant des outils de la théorie des graphes, nous avons aussi démontré que les MaOris sont des hubs interconnectés à longue portée dans le réseau structurel, fondamentaux pour l’organisation 3D du génome et nous avons développé une méthodologie multi-échelle basée sur les ondelettes sur graphes pour délimiter objectivement des unités structurelles à partir des données Hi-C. Ce travail nous permet de discuter de la relation entre les domaines de réplication et les unités structurelles entre les différentes lignées cellulaires humaines<br>The replication program of about one half of mammalian genomes is characterized by megabase-sized replication U/N-domains. These domains are bordered by master replication origins (MaOris) corresponding to ~200 kb regions of open chromatin favorable for early initiation of replication and transcription. Thanks to recent high-throughput chromosome conformation capture technologies (Hi-C), 3D co-localization frequency matrices between all genome loci are now experimentally determined. It appeared that U/N-domains were related to the organization of the genome into structural units. In this thesis, we performed a combined analysis of human Hi-C data and replication timing profiles to further explore the structure/function relationships in the nucleus. This led us to describe novel large (>3 Mb) replication timing split-U domains also bordered by MaOris, to demonstrate that the replication wave initiated at MaOris only depends of the time during S phase and to show that chromatin folding is compatible with a 3D equilibrium in early-replicating euchromatin regions turning to a 2D equilibrium in the late-replicating heterochromatin regions associated to nuclear lamina. Representing Hi-C co-localization matrices as structural networks and deploying graph theoretical tools, we also demonstrated that MaOris are long-range interconnected hubs in the structural network, central to the 3D organization of the genome and we developed a novel multi-scale methodology based on graph wavelets to objectively delineate structural units from Hi-C data. This work allows us to discuss the relationship between replication domains and structural units across different human cell lines
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Marie-Nelly, Hervé. "A probabilistic approach for genome assembly from high-throughput chromosome conformation capture data." Paris 6, 2013. http://www.theses.fr/2013PA066714.
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Les approches modernes de séquençage d’adn ne permettent pas la lecture de fragments de plus de quelques kb. De ce fait, ont été développés des méthodes algorithmique permettant de former de plus grandes séquences ˆ partir de ces petits fragments. Nous avons développé une nouvelle méthodologie d’assemblage de génome basée sur le HiC. Le HiC est une procédure biochimique permettant l’inférence de la structure tridimensionelle d’un génome. Basée sur des probabilités bayesienne, notre méthode inverse le flux logique d’analyse de ces données. A partir des données 3D nous pouvons détecter et corriger les erreurs d’assemblages. Après avoir décrit le cadre mathématiques de la méthode, nous décrirons les résultats préliminaires obtenus sur des données simulées ainsi que des données expérimentales. En particulier nous montrerons une application concluante de la méthode sur le génome, encore non assemblé de trichoderma reesei, un champignon utilisé dans l’industrie énergÉtique<br>Computational methods are needed to assemble entire genomes from large numbers of short DNA strands. However, standard algorithms that piece together DNA strands with overlapping sequences face important limitations due, for example, to regions of repeated sequences, thus leaving many genome assemblies incomplete. We set out to develop a new methodology for genome assembly that promises to address some of these limitations. The method is based on Hi-C, a recent biochemical technique initially developed to analyse the 3D architecture of genomes. In standard Hi-C studies, a previously assembled genome is used to identify chimeric sequences among the ligation products, and map them to pairs of chromosomal loci, thereby yielding a genome-wide matrix of contact frequencies. Our method essentially reverses this approach: Hi-C data are used to test for the physical continuity of the chromatin fibre as expected from a set of DNA segments (representing either a complete or incomplete chromosomal set). This procedure improves genome assembly and/or identification of structural variants in re-sequenced genomes. Our approach uses a Bayesian framework that assigns probabilities to different assemblies based on the experimental Hi-C data and on laws describing the physical properties of chromosomes. We will explain the methodology and the developed algorithms and provide results of applications to simulated and real Hi-C data from mutant and natural structural variants of yeast and fungi. We also have developed algorithm that allow us to identify functional sequences in genomes from genome wide contact matrices
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Marti, Marimon Maria Eugenia. "3D genome conformation and gene expression in fetal pig muscle at late gestation." Thesis, Toulouse, INPT, 2018. http://www.theses.fr/2018INPT0099.
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Dans le secteur de l’élevage porcin, les truies ont été sélectionnées pendant des décennies pour leur prolificité afin de maximiser la production de viande. Cependant, cette sélection a été associée à une mortalité plus élevée des nouveau-nés. Dans ce contexte, le muscle foetal squelettique est essentiel à la survie du porcelet, car il est nécessaire pour les fonctions motrices et la thermorégulation. Par ailleurs, la structure tridimensionnelle du génome s'est avérée jouer un rôle important dans la régulation de l'expression génique. Ainsi, dans ce projet, nous nous sommes intéressés à la conformation 3D du génome et l'expression des gènes dans les noyaux des cellules musculaires porcines à la fin de la gestation. Nous avons initialement développé une approche originale dans laquelle nous avons combiné des données transcriptomiques avec des informations de localisations nucléaires (évaluées par 3D DNA FISH) d'un sous-ensemble de gènes, afin de construire des réseaux de gènes co-exprimés. Cette étude a révélé des associations nucléaires intéressantes impliquant les gènes IGF2, DLK1 et MYH3, et a mis en évidence un réseau de gènes interdépendants spécifiques du muscle impliqués dans le développement et la maturité du muscle foetal. Nous avons ensuite évalué la conformation globale du génome dans les noyaux musculaires à 90 jours et à 110 jours de gestation en utilisant la méthode de capture de conformation de chromatine à haut débit (Hi-C) couplée au séquençage. Cette étude a permis d'identifier des milliers de régions génomiques présentant des différences significatives dans la conformation 3D entre les deux âges gestationnels. Fait intéressant, certaines de ces régions génomiques impliquent les régions télomériques de plusieurs chromosomes qui semblent former des clusters préférentiellement à 90 jours. Plus important, les changements observés dans la structure du génome sont associés de manière significative à des variations d'expression géniques entre le 90ème et le 110ème jour de gestation<br>In swine breeding industry, sows have been selected for decades on their prolificacy in order to maximize meat production. However, this selection is associated with a higher mortality of newborns. In this context, the skeletal fetal muscle is essential for the piglet’s survival, as it is necessary for motor functions and thermoregulation. Besides, the three-dimensional structure of the genome has been proven to play an important role in gene expression regulation. Thus, in this project, we have focused our interest on the 3D genome conformation and gene expression in porcine muscle nuclei at late gestation. We have initially developed an original approach in which we combined transcriptome data with information of nuclear locations (assessed by 3D DNA FISH) of a subset of genes, in order to build gene co expression networks. This study has revealed interesting nuclear associations involving IGF2, DLK1 and MYH3 genes, and highlighted a network of muscle specific interrelated genes involved in the development and maturity of fetal muscle. Then, we assessed the global 3D genome conformation in muscle nuclei at 90 days and 110 days of gestation by using the High-throughput Chromosome Conformation Capture (Hi¬ C) method. This study has allowed identifying thousands of genomic regions showing significant differences in 3D conformation between the two gestational ages. Interestingly, some of these genomic regions involve the telomeric regions of several chromosomes that seem to be preferentially clustered at 90 days. More important, the observed changes in genome structure are significantly associated with variations in gene expression between the 90th and the 110th days of gestation
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Nilsson, Johan. "Membrane protein topology : prediction, experimental mapping and genome-wide analysis /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-963-3/.
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Jurneczko, Ewa. "Resolving intrinsically disordered proteins of the cancer genome with ion mobility mass spectrometry." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/8844.
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For proteins the link between their structure and their function is a central tenet of biology. A common approach to understanding protein function is to ‘solve’ its structure and subsequently probe interactions between the protein and its binding partners. The first part of this approach is non-trivial for proteins where localised regions or even their entire structure fail to fold into a three-dimensional structure and yet they possess function. These so called intrinsically or inherently disordered proteins (IDP’s) or intrinsically disordered regions (IDR’s) constitute up to 40% of all expressed proteins. IDPs which have crucial roles in molecular recognition, assembly, protein modification and entropic chain activities, are often dynamic with respect to both conformation and interaction, so in the course of a protein’s ‘lifespan’ it will sample many configurations and bind to several targets. For these proteins, there is a need to develop new methods for structure characterization which exploit their biophysical properties. The solvent free environment of a mass spectrometer is ideally suited to the study of intrinsic interactions and how they contribute to structure. Ion mobility mass spectrometry is uniquely able to observe the range of structures an IDP can occupy, and also the effect of selected binding partners on altering this conformational space. This thesis details the technique of ion mobility mass spectrometry and illustrates its use in assessing the relative disorder of p53 protein. The tumour suppressor p53 is at the hub of a plethora of signalling pathways that maintain the integrity of the human genome and regulate the cell cycle. Deregulation of this protein has a great effect on carcinogenesis as mutated p53 can induce an amplified epigenetic instability of tumour cells, facilitating and accelerating the evolution of the tumour. Herein mass spectrometry provides a compelling, detailed insight into the conformational flexibility of the p53 DNA-binding domain. The plasticity of the p53 DNA-binding domain is reflected in the existence of more than one conformation, independent of any conformational changes prompted by binding. The in vacuo conformational phenotypes exhibited by common cancer-associated mutations are determined and the second-site suppressor mutation from loop L1, H115N, is probed whether it could trigger conformational changes in p53 hotspot cancer mutations. The structural basis of the binding promiscuity of p53 protein is investigated; of particular interest is the molecular interaction of the p53 N-terminus with the oncoprotein murine double minute 2, as well as with the antiapoptotic factor B-cell lymphoma-extralarge.
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Schröder, Wiebke [Verfasser]. "Athletic performance and conformation in Hanoverian warmblood horses - population genetic and genome-wide association analyses / Wiebke Schröder." Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2010. http://d-nb.info/1009653288/34.
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LUCINI, FEDERICA. "Unconventional nuclear architecture in CD4+ T lymphocytes uncouples chromatin solubility from function." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2020. http://hdl.handle.net/10281/262913.
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Nei nuclei delle cellule eucarioti, l'informazione genetica codificata nel DNA è concentrata nel microscopico volume nucleare in forma di cromatina, un complesso di DNA e proteine. I meccanismi molecolari che gestiscono la compattazione e il ripiegamento della cromatina e che consentono l'espressione mirata delle porzioni di genoma necessarie alle attività della cellula sono noti come ‘epigenoma’. L’azione dell’epigenoma determina un avvolgimento e un posizionamento nucleare della cromatina specifico per ogni tipo cellulare, con aree dense e trascrizionalmente inattive (eterocromatina) ed aree meno dense, ricche di geni e trascrizionalmente attive (eucromatina).
In questo nostro lavoro descriviamo l'organizzazione della cromatina nel nucleo di diverse popolazioni cellulari e ne analizziamo alcuni aspetti fisiologici e patologici.
Innanzitutto, studiando le cellule staminali muscolari di topi privi della proteina strutturale nucleare lamina-A/C, descriviamo un irregolare processo di differenziamento dovuto alla redistribuzione dei repressori trascrizionali del gruppo Polycomb (PcG proteins), che dai i loro geni target si diffondono verso regioni cromatiniche fiancheggianti. La conseguente alterazione nell’espressione genica causa l’esaurimento prematuro della riserva di cellule staminali quiescenti e l’accumulo di grasso intramuscolare, portando a una senescenza accelerata e alla distrofia muscolare.
D’altro canto, anche il progressivo accumulo di una forma aberrante di lamina-A, la progerina, caratteristica della sindrome di Hutchinson-Gilford (HGPS), causa gravi alterazioni nella struttura della cromatina. In particolare, la progerina interferisce con le strutture eterocromatiniche periferiche associate alla lamina nucleare, i Lamina Associated Domains (LADs). Per il nostro secondo progetto abbiamo sviluppato un nuovo metodo, SAMMY-seq, basato sull’high-throughput sequencing di frazioni di cromatina con diversa solubilità. Tramite questa tecnologia, individuiamo alterazioni nella solubilità dell’eterocromatina in fibroblasti primari derivanti da pazienti progerici in uno stadio precoce di malattia. I cambiamenti strutturali osservati a questo stadio non alterano la deposizione del marcatore eterocromatinico H3K9me3, ma sono associati a variazioni sito-specifiche nella regolazione trascrizionale di geni target delle PcG proteins.
Infine, ottimizzando ulteriormente il protocollo di SAMMY-seq, nel nostro terzo progetto mostriamo un’organizzazione non convenzionale della cromatina nei linfociti T CD4+ quiescenti derivanti da sangue periferico di donatori. In queste cellule, l’eterocromatina risulta sensibile alla digestione enzimatica operata dalla DNAsi, mentre l’eucromatina si rivela resistente a diversi processi di estrazione. Un’analisi preliminare del contenuto di questi compartimenti indica la presenza, nell’eucromatina, dei geni specifici per l’attivazione linfocitaria, oltre che dei geni attivi. Ulteriori studi chiariranno il ruolo di questa organizzazione non convenzionale della cromatina nella funzione cellulare linfocitaria.<br>In every eukaryotic cell, the genomic information coded in the DNA is packed into the small nuclear volume as chromatin, a complex of DNA and proteins. The ensemble of molecular mechanisms that organize chromatin compaction and allow the specific expression of the portions of genome useful for cell’s biological functions is known as the epigenome. As a result of epigenome activity, chromatin is folded and positioned in the nucleus in a cell-specific manner, generating areas of highly compacted, repressed, heterochromatin and areas of decondensed, gene-rich and transcriptionally active, euchromatin.
In our work, we describe chromatin organization in different cell populations and analyse some of its implications in the physiological functions and pathological dysfunctions of the cell.
In the first project, we focus on murine muscle stem cells lacking the nuclear structural protein Lamin A/C. We show their irregular differentiation program, due to a spreading of Polycomb group (PcG) of proteins repressors from their target genes over the flanking regions. The consequent alteration in gene expression cause premature exhaustion of quiescent stem cells and accumulation of intramuscular fat, resulting in accelerated senescence and muscular dystrophy progression.
On the other hand, the progressive accumulation of a Lamin A aberrant form, Progerin, in Hutchinson-Gilford progeria syndrome (HGPS) also leads to chromatin structure disruption. In particular, it interferes with Lamina Associated Domains (LADs), the peripheral heterochromatin structures associated to the nuclear lamina. For our second project, we develop a new method, SAMMY-seq, based on high-throughput sequencing of chromatin fractions of different solubility. Thanks to this technology, we highlight early changes in heterochromatin accessibility in human HGPS primary fibroblasts. This early structural changes do not alter the deposition of the H3K9me3 heterochromatin mark but are associated with site-specific variations in the PcG-dependent transcriptional regulation.
Finally, further improving SAMMY-seq technology, in our third project we describe an unconventional genome organization in resting human CD4+ T lymphocytes extracted from the peripheral blood of healthy donors. In these cells, heterochromatin is sensitive to DNAse digestion while euchromatin is resistant to serial processes of extraction. Preliminary analysis of the content of these compartments suggests that euchromatin contains, beside the actively transcribed genes, also inactive genes specific for lymphocyte activation. Further studies will elucidate the role of this unconventional chromatin organization in lymphocytes functions.
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Lazar-Stefanita, Luciana. "Functional reorganization of the yeast genome during the cell cycle." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066400/document.
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Des décennies d'études ont montré que la structure de la chromatine est étroitement liée aux processus métaboliques de l'ADN. Une bonne organisation des chromosomes tout au long du cycle cellulaire est particulièrement importante pour assurer le maintien de l'intégrité de l'ADN. Le but de mon projet de doctorat était de caractériser dans quelle mesure la réorganisation de la chromatine pendant le cycle cellulaire pourrait influencer la stabilité des chromosomes. Pour ce faire, nous avons d'abord effectué une étude complète de la réorganisation des chromosomes de la levure modèle Saccharomyces cerevisiae pendant tout un cycle cellulaire. Ce travail, en plus de récapituler les caractéristiques chromosomiques attendues, a conduit à la caractérisation de structures chromosomiques particulières, telle qu'une boucle d'ADN reliant l'ADNr et les centromères. Le rôle des complexes SMC et des microtubules a été étudié en profondeur. Une deuxième partie de mon travail a porté sur la description de l'organisation de la chromatine de cellules qui ont quitté le cycle cellulaire prolifératif et sont entrées en quiescence. Nous avons ainsi caractérisé le statut dense de l'hétérochromatine silencieuse dans des loci spécifiques tels que les télomères. Enfin, nous avons essayé de mieux comprendre l'interaction fonctionnelle entre la stabilité chromosomique et l'architecture 3D du génome durant la réplication en étudiant la stabilité génomique à des sites de pause de réplication. Nos résultats indiquent une adaptabilité frappante des structures de réplication sous différentes contraintes. Le travail futur vise à cartographier les réarrangements chromosomiques dépendants de la réplication<br>Decades of studies showed that chromatin structure is tightly linked to DNA related metabolic processes, through the dynamic regulation of a myriad of molecular factors. The proper organization of chromosomes is notably important to ensure the maintenance of DNA integrity during cell cycle progression. Using the model S. cerevisiae, the aim of my PhD project was to characterize to which extent chromatin reorganization during the cell cycle may influence chromosome stability. To do so, we first generated a comprehensive genome-wide study of the reorganization of yeast’s chromosomes during an entire cell cycle. This work, besides recapitulating expected chromosomal features of the replication and mitotic stages, led to the characterization of peculiar chromosome structures such as a DNA loop bridging the rDNA and the centromeres. The role of structural maintenance of chromosomes (SMC) complexes and of microtubules were thoroughly investigated. A second part of my work focused on describing features of the chromatin organization of cells that exited the proliferative cell cycle and entered into quiescence. We characterized the dense status of silenced heterochromatin at specific loci, such as telomeres, in relation to the silent information regulators (SIRs). Finally, we tried to achieve a better understanding of the functional interplay between chromosome stability and the 3D genome architecture during replication, by investigating the genomic stability at replication pausing sites. Overall, our results point at a striking plasticity of replication structures to different stresses. Future work aims to map replication-dependent chromosomal rearrangements on the genomic maps
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Lajoie, Bryan R. "Computational Approaches for the Analysis of Chromosome Conformation Capture Data and Their Application to Study Long-Range Gene Regulation: A Dissertation." eScholarship@UMMS, 2016. http://escholarship.umassmed.edu/gsbs_diss/833.
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Over the last decade, development and application of a set of molecular genomic approaches based on the chromosome conformation capture method (3C), combined with increasingly powerful imaging approaches have enabled high resolution and genome-wide analysis of the spatial organization of chromosomes. The aim of this thesis is two-fold; 1), to provide guidelines for analyzing and interpreting data obtained from genome-wide 3C methods such as Hi-C and 3C-seq and 2), to leverage the 3C technology to solve genome function, structure, assembly, development and dosage problems across a broad range of organisms and disease models.
First, through the introduction of cWorld, a toolkit for manipulating genome structure data, I accelerate the pace at which *C experiments can be performed, analyzed and biological insights inferred. Next I discuss a set of practical guidelines one should consider while planning an experiment to study the structure of the genome, a simple workflow for data processing unique to *C data and a set of considerations one should be aware of while attempting to gain insights from the data.
Next, I apply these guidelines and leverage the cWorld toolkit in the context of two dosage compensation systems. The first is a worm condensin mutant which shows a reduction in dosage compensation in the hermaphrodite X chromosomes. The second is an allele-specific study consisting of genome wide Hi-C, RNA-Seq and ATAC-Seq which can measure the state of the active (Xa) and inactive (Xi) X chromosome. Finally I turn to studying specific gene – enhancer looping interactions across a panel of ENCODE cell-lines.
These studies, when taken together, further our understanding of how genome structure relates to genome function.
Books on the topic "Genome conformation"
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Frishman, Dmitrij. Modern genome annotation: The BioSapiens Network. Springer, 2009.
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R, Pennington S., and Dunn M. J, eds. Proteomics: From protein sequence to function. BIOS, 2001.
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1927-, Jollès Pierre, and Jörnvall Hans, eds. Proteomics in functional genomics: Protein structure analysis. Birkhäuser Verlag, 2000.
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Ryoiti, Kiyama, Shimizu Mitsuhiro, Hirose Susumu, and Transworld Research Network (Trivandrum, India), eds. DNA structure, chromatin and gene expression. Transworld Research Network, 2006.
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H, Lundstrom Kenneth, ed. Structural genomics on membrane proteins. Taylor & Francis, 2006.
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Joachimiak, Andrzej. Structural Genomics, Part B. Elsevier Science & Technology Books, 2009.
Find full textBook chapters on the topic "Genome conformation"
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Zhigulev, Artemy, and Pelin Sahlén. "Targeted Chromosome Conformation Capture (HiCap)." In Spatial Genome Organization. Springer US, 2022. http://dx.doi.org/10.1007/978-1-0716-2497-5_5.
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Rebouissou, Cosette, Séphora Sallis, and Thierry Forné. "Quantitative Chromosome Conformation Capture (3C-qPCR)." In Spatial Genome Organization. Springer US, 2022. http://dx.doi.org/10.1007/978-1-0716-2497-5_1.
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Nanni, Luca. "Computational Inference of DNA Folding Principles: From Data Management to Machine Learning." In Special Topics in Information Technology. Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-85918-3_7.
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AbstractDNA is the molecular basis of life and would total about three meters if linearly untangled. To fit in the cell nucleus at the micrometer scale, DNA has, therefore, to fold itself into several layers of hierarchical structures, which are thought to be associated with functional compartmentalization of genomic features like genes and their regulatory elements. For this reason, understanding the mechanisms of genome folding is a major biological research problem. Studying chromatin conformation requires high computational resources and complex data analyses pipelines. In this chapter, we first present the PyGMQL software for interactive and scalable data exploration for genomic data. PyGMQL allows the user to inspect genomic datasets and design complex analysis pipelines. The software presents itself as a easy-to-use Python library and interacts seamlessly with other data analysis packages. We then use the software for the study of chromatin conformation data. We focus on the epigenetic determinants of Topologically Associating Domains (TADs), which are region of high self chromatin interaction. The results of this study highlight the existence of a “grammar of genome folding” which dictates the formation of TADs and boundaries, which is based on the CTCF insulator protein. Finally we focus on the relationship between chromatin conformation and gene expression, designing a graph representation learning model for the prediction of gene co-expression from gene topological features obtained from chromatin conformation data. We demonstrate a correlation between chromatin topology and co-expression, shedding a new light on this debated topic and providing a novel computational framework for the study of co-expression networks.
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Polles, Guido, Nan Hua, Asli Yildirim, and Frank Alber. "Genome Structure Calculation through Comprehensive Data Integration." In Modeling the 3D Conformation of Genomes. CRC Press, 2019. http://dx.doi.org/10.1201/9781315144009-11.
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Papale, Andrea, and Angelo Rvosay. "Structure and Microrheology of Genome Organization: From Experiments to Physical Modeling." In Modeling the 3D Conformation of Genomes. CRC Press, 2019. http://dx.doi.org/10.1201/9781315144009-7.
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Vietri Rudan, Matteo, Suzana Hadjur, and Tom Sexton. "Detecting Spatial Chromatin Organization by Chromosome Conformation Capture II: Genome-Wide Profiling by Hi-C." In Methods in Molecular Biology. Springer New York, 2016. http://dx.doi.org/10.1007/7651_2015_261.
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Di Stefano, Marco, and Marc A. Marti-Renom. "Restraint-Based Modeling of Genomes and Genomic Domains." In Modeling the 3D Conformation of Genomes. CRC Press, 2019. http://dx.doi.org/10.1201/9781315144009-10.
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Brouwer, Rutger W. W., Mirjam C. G. N. van den Hout, Wilfred F. J. van IJcken, Eric Soler, and Ralph Stadhouders. "Unbiased Interrogation of 3D Genome Topology Using Chromosome Conformation Capture Coupled to High-Throughput Sequencing (4C-Seq)." In Methods in Molecular Biology. Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4939-6518-2_15.
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Kawaguchi, Akane, and Elly M. Tanaka. "Chromosome Conformation Capture for Large Genomes." In Methods in Molecular Biology. Springer US, 2022. http://dx.doi.org/10.1007/978-1-0716-2659-7_20.
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Dekker, Job. "Chromosome Folding: Contributions of Chromosome Conformation Capture and Polymer Physics." In Modeling the 3D Conformation of Genomes. CRC Press, 2019. http://dx.doi.org/10.1201/9781315144009-1.
Full textConference papers on the topic "Genome conformation"
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"Maps of chromatin conformation in the cerebral cortex." In Bioinformatics of Genome Regulation and Structure/Systems Biology (BGRS/SB-2022) :. Institute of Cytology and Genetics, the Siberian Branch of the Russian Academy of Sciences, 2022. http://dx.doi.org/10.18699/bgrs/sb-2022-056.
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"Maps of chromatin conformation in the cerebral cortex." In Bioinformatics of Genome Regulation and Structure/Systems Biology (BGRS/SB-2022) :. Institute of Cytology and Genetics, the Siberian Branch of the Russian Academy of Sciences, 2022. http://dx.doi.org/10.18699/sbb-2022-056.
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Nagpal, S., V. Krishna, X. Yin, et al. "OP0289 Integration of chromatin conformation, transcriptome and genome-wide landscape of brd2 and brd4 binding motifs identifies mechanisms of bet inhibitor action in rheumatoid arthritis synovial fibroblasts." In Annual European Congress of Rheumatology, EULAR 2018, Amsterdam, 13–16 June 2018. BMJ Publishing Group Ltd and European League Against Rheumatism, 2018. http://dx.doi.org/10.1136/annrheumdis-2018-eular.7388.
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Xu, Yangqing, and Gang Bao. "Protein Conformational Changes Under Applied Forces." In ASME 1999 International Mechanical Engineering Congress and Exposition. American Society of Mechanical Engineers, 1999. http://dx.doi.org/10.1115/imece1999-0408.
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Abstract Recent studies confirm that stresses, including that due to gravity, tension, compression, pressure, and shear influence cell growth, differentiation, secretion, movement, signal transduction, and gene expression. Yet, little is known about how cells sense the mechanical stresses or deformations, and convert these mechanical signals into biological or biochemical responses. A possible mechno-chemical coupling mechanism involves protein conformational changes under mechanical forces. Our hypothesis is that mechanical forces can cause large changes of the conformation of proteins, which in turn can influence receptor-ligand binding. To test this hypothesis, molecular dynamics simulations and biochemical assays are performed.
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"3D-MAGs – spatial conformations of individual microbial genomes reconstructed from Hi-C metagenomes." In Bioinformatics of Genome Regulation and Structure/Systems Biology (BGRS/SB-2022) :. Institute of Cytology and Genetics, the Siberian Branch of the Russian Academy of Sciences, 2022. http://dx.doi.org/10.18699/sbb-2022-065.
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"Conformational dynamics in methylated DNA repair by human Fe(II)/alpha-ketoglutarate dependent dioxygenases ALKBH2 and ALKBH3." In Bioinformatics of Genome Regulation and Structure/ Systems Biology. institute of cytology and genetics siberian branch of the russian academy of science, Novosibirsk State University, 2020. http://dx.doi.org/10.18699/bgrs/sb-2020-352.
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"The pre-steady state analysis of human terminal deoxynucleotidyltransferase conformational dynamics under DNA synthesis." In Bioinformatics of Genome Regulation and Structure/Systems Biology (BGRS/SB-2022) :. Institute of Cytology and Genetics, the Siberian Branch of the Russian Academy of Sciences, 2022. http://dx.doi.org/10.18699/sbb-2022-591.
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"Application of X-Ray, SAXS and essential dynamics simulations to study conformational transitions of oligopeptidase B." In Bioinformatics of Genome Regulation and Structure/Systems Biology (BGRS/SB-2022) :. Institute of Cytology and Genetics, the Siberian Branch of the Russian Academy of Sciences, 2022. http://dx.doi.org/10.18699/sbb-2022-155.
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Kim, Moon K., Byeongsoo Lim, and Wing Kam Liu. "Multiscale Elastic Network Model for Macromolecular Machines." In ASME 2010 First Global Congress on NanoEngineering for Medicine and Biology. ASMEDC, 2010. http://dx.doi.org/10.1115/nemb2010-13090.
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In the early year of this century the human genome sequencing project was successfully completed so that we can understand all the human genes and their corresponding protein sequences. Now our interests have naturally moved from genetics to proteomics in which we challenge to elucidate the relationship between functions and structures of proteins. In particular, understanding large conformational changes occurring at molecular machinery systems or protein assemblies have received great attentions. However, it has been rarely studied both experimentally and theoretically because of limitation of experimental setup for capturing real time protein dynamics and computing power, respectively.
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Geddes, V. A., G. V. Louie, G. D. Brayer, and R. T. A. MacGillivray. "MOLECULAR BASIS OF HEMOPHILIA B: IDENTIFICATION OF THE DEFECT IN FACTOR IX VANCOUVER." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643872.
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Factor IX Vancouver (fIX-V) is the cause of a moderate form of hemophilia B. An individual presenting with this disorder had 2.6% of normal procoagulant activity in his plasma but had 62% of the normal factor IX antigen level. Specific antibodies showed that fIX-V contains epitopes for both the heavy and light chains of factor IXa. To identify the defect involved, DNA was isolated from the lymphocytes of the male hemophiliac. Southern blot analysis using a full-length factor IX cDNA as a hybridization probe showed no gross differences between the fIX-V gene and the normal factor IX gene. The DNA from the hemophiliac was then partially digested with Sau3A and the resulting fragments (10-20kbp in size) were ligated into the BamHI site of λEMBL3. The DNA was then packaged into phage particles in vitro, and the recombinant phage were screened with the factor IX cDNA as a probe. Eight phage were isolated that contained overlapping DNA covering the complete gene for fIX-V. DNA sequence analysis of the protein-encoding regions, the intron/exon junctions and 5'-and 3'-flanking sequences revealed a single nucleotide change from the normal factor IX gene. The codon for amino acid 397 was changed from ATA (lie) to ACA (Thr). This mutation is in the catalytic domain of factor IXa and is novel amongst those hemophilia B mutations reported to date. Based on the known three dimensional structures of the pancreatic serine proteases, trypsin, elastase and chymotrypsin, models have been constructed for the structures of the catalytic domains of both the normal and Thr-397 mutant of factor IXa. These results suggest that the Thr-397 mutation may alter the conformation of the substrate binding region in the active site of factor IXa Vancouver through the formation of a hydrogen bond between the hydroxyl group of the Thr-397 side chain and the main chain carbonyl group of Trp-385. The postulated conformational change would lead to reduced binding affinity for the factor IXa substrate resulting in a reduction in the catalytic activity of fIXa-Vancouver.Supported in part by grants from the Medical Research Council of Canada (to GDB and RTAM).
Reports on the topic "Genome conformation"
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Prusky, Dov, Nancy P. Keller, and Amir Sherman. global regulation of mycotoxin accumulation during pathogenicity of Penicillium expansum in postharvest fruits. United States Department of Agriculture, 2014. http://dx.doi.org/10.32747/2014.7600012.bard.
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Background to the topic- Penicilliumas a postharvest pathogen and producer of the mycotoxin PAT. Penicilliumspp. are destructive phytopathogens, capable of causing decay in many deciduous fruits, during postharvest handling and storage; and the resulting losses can amount to 10% of the stored produce and the accumulation of large amounts of the mycotoxinpatulin. The overall goal of this proposal is to identify critical host and pathogen factors that modulate P. expansummycotoxin genes and pathways which are required for PAT production and virulence. Our preliminary results indicated that gluconic acid are strongly affecting patulin accumulation during colonization. P. expansumacidifies apple fruit tissue during colonization in part through secretion of gluconic acid (GLA). Several publications suggested that GLA accumulation is an essential factor in P. expansumpathogenicity. Furthermore, down regulation of GOX2 significantly reduced PAT accumulation and pathogenicity. PAT is a polyketide and its biosynthesis pathway includes a 15-gene cluster. LaeA is a global regulator of mycotoxin synthesis. It is now known that patulin synthesis might be subjected to LaeA and sometimes by environmental sensing global regulatory factors including the carbon catabolite repressor CreA as well as the pH regulator factor PacC and nitrogen regulator AreA. The mechanisms by which LaeA regulates patulin synthesis was not fully known and was part of our work. Furthermore, the regulatory system that controls gene expression in accordance with ambient pH was also included in our work. PacC protein is in an inactive conformation and is unable to bind to the promoter sites of the target genes; however, under alkaline growth conditions activated PacC acts as both an activator of alkaline-expressed genes and a repressor of acid-expressed genes. The aims of the project- This project aims to provide new insights on the roles of LaeA and PacC and their signaling pathways that lead to GLA and PAT biosynthesis and pathogenicity on the host. Specifically, our specific aims were: i) To elucidate the mechanism of pH-controlled regulation of GLA and PAT, and their contribution to pathogenesis of P. expansum. We are interested to understanding how pH and/or GLA impact/s under PacC regulation affect PAT production and pathogenesis. ii) To characterize the role of LaeA, the global regulator of mycotoxin production, and its effect on PAT and PacC activity. iii) To identify the signaling pathways leading to GLA and PAT synthesis. Using state- of-the-art RNAseq technologies, we will interrogate the transcriptomes of laeAand pacCmutants, to identify the common signaling pathways regulating synthesis of both GLA and PAT. Major conclusions, solutions, achievements- In our first Aim our results demonstrated that ammonia secreted at the leading edge of the fungal colony induced transcript activation of the global pH modulator PacC and PAT accumulation in the presence of GLA. We assessed these parameters by: (i) direct exogenous treatment of P. expansumgrowing on solid medium; (ii) direct exogenous treatment on colonized apple tissue; (iii) growth under self-ammonia production conditions with limited carbon; and (iv) analysis of the transcriptional response to ammonia of the PAT biosynthesis cluster. Ammonia induced PAT accumulation concurrently with the transcript activation of pacCand PAT biosynthesis cluster genes, indicating the regulatory effect of ammonia on pacCtranscript expression under acidic conditions. Transcriptomic analysis of pH regulated processes showed that important genes and BARD Report - Project 4773 Page 2 of 10 functionalities of P. expansumwere controlled by environmental pH. The differential expression patterns of genes belonging to the same gene family suggest that genes were selectively activated according to their optimal environmental conditions to enable the fungus to cope with varying conditions and to make optimal use of available enzymes. Concerning the second and third Aims, we demonstrated that LaeA regulates several secondary metabolite genes, including the PAT gene cluster and concomitant PAT synthesis invitro. Virulence studies of ΔlaeAmutants of two geographically distant P. expansumisolates (Pe-21 from Israel and Pe-T01 from China) showed differential reduction in disease severity in freshly harvested fruit ranging from no reduction for Ch-Pe-T01 strains in immature fruit to 15–25% reduction for both strains in mature fruit, with the ΔlaeAstrains of Is-Pe-21 always showing a greater loss in virulence. Results suggest the importance of LaeA regulation of PAT and other secondary metabolites on pathogenicity. Our work also characterized for the first time the role of sucrose, a key nutritional factor present in apple fruit, as a negative regulator of laeAexpression and consequent PAT production in vitro. This is the first report of sugar regulation of laeAexpression, suggesting that its expression may be subject to catabolite repression by CreA. Some, but not all of the 54 secondary metabolite backbone genes in the P. expansumgenome, including the PAT polyketide backbone gene, were found to be regulated by LaeA. Together, these findings enable for the first time a straight analysis of a host factor that potentially activates laeAand subsequent PAT synthesis.
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McElwain, Terry F., Eugene Pipano, Guy H. Palmer, Varda Shkap, Stephn A. Hines, and Wendy C. Brown. Protection of Cattle against Babesiosis: Immunization against Babesia bovis with an Optimized RAP-1/Apical Complex Construct. United States Department of Agriculture, 1999. http://dx.doi.org/10.32747/1999.7573063.bard.
Full textAbstract:
Previous research and current efforts at control of babesiosis fall short of meeting the needs of countries where the disease is endemic, such as Israel, as well as the needs of exporting countries and countries bordering on endemic areas, such as the U.S. Our long-term goal is to develop improved methods of immunization against bovine babesiosis based on an understanding of the molecular mechanisms of immune protection and parasite targets of a protective immune response. In our previous BARD project, we established the basis for focusing on rhoptry antigens as components of a subunit vaccine against bovine babesiosis, and for additional research to better characterize rhoptry associated protein-1 (RAP-1) as a target of protective immunity. In this continuation BARD project, our objectives were to [1] optimize the immune response against RAP-1, and [2] identify additional rhoptry candidate vaccine antigens. The entire locus encoding B. bovis RAP-1 was sequenced, and the rap-1 open reading frame compared among several strains. Unlike B. bigemina, in which multiple gene copies with variant domains encode RAP-1, the B. bovis RAP-1 locus contains only two identical genes which are conserved among strains. Through testing of multiple truncated constructs of rRAP-1, one or more immunodominant T cell epitopes were mapped to the amino terminal half of RAP-1. At least one linear and one conformational B cell epitope have been demonstrated in the same amino terminal construct, which in B. bigemina RAP-1 also contains an epitope recognized by neutralizing antibody. The amine terminal half of the molecule represents the most highly conserved part of the gene family and contains motifs conserved broadly among the apicomplexa. In contrast, the carboxy terminal half of B. bovis RAP-1 is less well conserved and contains multiple repeats encoding a linear B cell epitope potentially capable of inducing an ineffective, T cell independent, type 2 immune response. Therefore, we are testing an amino terminal fragment of RAP-1 (RAP-1N) in an immunization trial in cattle. Cattle have beer immunized with RAP-1N or control antigen, and IL-12 with Ribi adjuvant. Evaluation of the immune response is ongoing, and challenge with virulent B. bovis will occur in the near future. While no new rhoptry antigens were identified, our studies did identify and characterize a new spherical body antigen (SBP3), and several heat shock proteins (HSP's). The SBP3 and HSP21 antigens stimulate T cells from immune cattle and are considered new vaccine candidates worthy of further testing. Overall, we conclude that a single RAP-1 vaccine construct representing the conserved amino terminal region of the molecule should be sufficient for immunization against all strains of B. bovis. While results of the ongoing immunization trial will direct our next research steps, results at this time are consistent with our long term goal of designing a subunit vaccine which contains only the epitopes relevant to induction of protective immunity. Parallel studies are defining the mechanisms of protective immunity. Apicomplexan protozoa, including babesiosis and malaria, cause persistent diseases for which control is inadequate. The apical organelles are defining features of these complex protozoa, and have been conserved through the evolutionary process, Past and current BARD projects on babesiosis have established the validity and potential of exploiting these conserved organelles in developing improved control methods applicable to all apicomplexan diseases.