Dissertations / Theses: 'Epigenetic memory'

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Magnell, Albert T. (Albert Thomas). "Epigenetic Memory of Mouse Intestinal Inflammation." Thesis, Massachusetts Institute of Technology, 2021. https://hdl.handle.net/1721.1/130670.

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Thesis: S.M., Massachusetts Institute of Technology, Department of Biology, 2021
Cataloged from the official PDF version of thesis.
Includes bibliographical references (pages 29-31).
The gut, encompassing one of the largest epithelial surfaces in the body, interacts with both biological and non-biological agents that can cause regular injury. Fortunately, the small intestinal epithelium has a remarkable capacity to repair itself after severe injury, due to the abundance of highly replicative stem cells housed in the intestinal crypt regions. Much remains to be understood about the activation processes of the repair mechanisms and to what extent the stem cells themselves can adapt to certain forms of damage, including molecular mechanisms related to gene regulation. Here, I show that in response to acute inflammation, chromatin in intestinal stem cells has increased accessibility around specific loci and that this state is maintained in some regions even after the epithelium has recovered from damage, suggesting the possibility of memory. Such epigenetic memory may confer some adaptive resiliency to subsequent damage.
by Albert T. Magnell.
S.M.
S.M. Massachusetts Institute of Technology, Department of Biology

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Chandramohan, Yalini. "Epigenetic mechanisms underlying stress-related learning and memory." Thesis, University of Bristol, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492580.

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An organism exposed to a stressful situation will undergo a complex array of physiological and behavioural changes aimed at the preservation of the organism during the stressful event as well as at stimulating adaptive and mnemonic processes in case the event would reoccur in the future. It is well-known that the hippocampus is highly involved in these processes. It has become clear in recent years that the processing of environmental stimuli in the hippocampus could be via changes in epigenetic state that lead to changes in neural function.

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Gookin, Dylon Kyle. "Epigenetic Mechanisms for Long-Term Memory Acquisition and Maintenance." Thesis, The University of Arizona, 2015. http://hdl.handle.net/10150/579049.

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In this review, we will explore the evidence that supports an epigenetic foundation for learning and memory. Through this, we will first review the basics of both learning and memory before delving into the foundational mechanisms for epigenetics. Understanding this, we will examine the evidence that suggest a link between epigenetics and long-term memory by observing two distinct directionalities: 1) the procession of learning into consolidation of a memory, and how this affects an organisms genetic code, and 2) the manifestation of change in behavior as a result of the aforementioned epigenetic changes to an organism's DNA. Beyond this, lapses in our current understanding will be discussed, and suggestions for future work will be outlined.

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Cherubini, A. "MYC-DRIVEN EPIGENETIC MEMORY MAINTAINS EMBRYONIC STEM CELL IDENTITY." Doctoral thesis, Università degli Studi di Milano, 2015. http://hdl.handle.net/2434/356044.

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Stem cells balance their self-renewal and differentiation potential by integrating environmental signals with the Transcriptional Regulatory Network (TRN). Moreover, the integration between extrinsic and intrinsic signals affects the maintenance of their epigenetic state, establishing an accurate cells identity. Although c-Myc transcription factors plays a major role in stem cells self-renewal and pluripotency, their mechanisms of actions and their ability to establish an epigenetic memory remains poorly defined. We addressed this point by profiling the epigenetic pattern and gene expression in Embryonic Stem (ES) cells, whose growth depends on conditional c-Myc activity. Here we show that c-Myc potentiates the Wnt/β- Catenin signaling pathway, which cooperates with the transcriptional regulatory network in sustaining ES cells self-renewal. c-Myc activation results in the transcriptional repression of Wnt antagonists Dkk1 and Sfrp1 through the direct recruitment of PRC2 on these targets. We found that, through these molecular mechanisms, c-Myc promotes pluripotency and self-renewal of ES cells by activating an alternative epigenetic program. Finally our data suggest that the consequent potentiation of the autocrine Wnt/β-Catenin signaling induces the transcriptional activation of the endogenous Myc family members, which in turn activates a Myc-driven self-reinforcing circuit. Thus, our data unravel a Myc-dependent selfpropagating epigenetic memory in the maintenance of ES cell identity.

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Kłosin, Adam 1985. "Mechanism and dynamics of transgenerational epigenetic memory in Caenorhabditis elegans." Doctoral thesis, Universitat Pompeu Fabra, 2015. http://hdl.handle.net/10803/482206.

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Desde Darwin y Lamarck, a los biólogos les ha intrigado la posibilidad de que rasgos adquiridos debido al ambiente pudieran ser heredados. Se han descrito muchos ejemplos de este tipo debidos a perturbaciones del ambiente y transmitidos durante generaciones en numerosas especies, aunque por el momento no se conoce su regulación a nivel molecular. Usando C. elegans como modelo demostramos que el aumento de la expresión de un transgén artificial en células somáticas inducido por altas temperaturas es conservado durante múltiples generaciones. Esta memoria epigenética está regulada por la transmisión entre generaciones de dos memorias epigenéticas: el principal regulador de los niveles de expresión en la siguiente generación es la transmisión en cis de la modificación de la histona H3K9me3, mientras que los represores RNA pequeños (dsRNA) se heredan en trans y actúan de mediadores en la restitución del estado reprimido de la cromatina. Además, la puesta a cero epigenética es reforzada por la comunicación desde células somáticas a germinales regulada por el canal de dsRNA SID-1. También demostramos finalmente que un estrés en la replicación del DNA durante el desarrollo embrionario interfiere con la transmisión epigenética del estado reprimido de la cromatina. Estos resultados contribuyen a aumentar el conocimiento que tenemos de la herencia epigenética y la posible puesta a cero de los rasgos adquiridos debidos a cambios en el ambiente.
Since Darwin and Lamarck, biologists have been intrigued by the possibility of the inheritance of environmentally-acquired traits. Examples of inter-generational transmission of traits induced by an environmental perturbation have been reported in multiple species, but the molecular mechanisms governing these responses remain obscure. Using C. elegans as a model system we demonstrate that high temperature-induced increase in expression from a somatically expressed transgene array persists for multiple generations. This epigenetic memory is governed by transgenerational transmission of two conflicting epigenetic memories: H3K9me3 histone marks are inherited in cis and act as the major determinant of expression levels in the next generation, whereas repressive small RNAs are inherited in trans and mediate restoration of the repressed state. In addition, epigenetic resetting is reinforced by soma to germline communication mediated by the dsRNA channel SID-1. Finally, we discovered that replication stress during early embryonic development interferes with epigenetic inheritance of a repressed state. These findings contribute to our understanding of the epigenetic inheritance and eventual resetting of environmentally acquired traits.

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Boudadi, Elsa. "Histone modification, gene regulation and epigenetic memory in embryonic stem cells." Thesis, University of Birmingham, 2011. http://etheses.bham.ac.uk//id/eprint/3160/.

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Histone modifications are thought to act as a layer of epigenetic information, because of their strong association with gene expression, and their potential role in transcriptional memory. However, although specific histone modifications correlate with transcriptional status, whether they play a causative role or act in the long term inheritance of gene expression patterns is unclear. In order to explore this, the histone deacetylase inhibitor valproic acid (VPA) was used to induce hyperacetylation of histones in embryonic stem cells. Surprisingly, although global levels of acetyl marks were highly increased by VPA treatment (up to 16-fold), only 10% of genes showed transcriptional changes. Interestingly, these global changes in histone modification were not reflected in the changes at individual genes where increases in acetylation were rarely greater than 2-fold. Furthermore, changes in acetylation levels did not correlate with transcriptional effects. Wash-out experiments showed that transient VPA treatment could not induce long term effects on transcription, even during ES cell differentiation when histone modifications play a crucial role. Finally, the role of polycomb silencing in the response to VPA treatment was assessed using an ES cell line in which the polycomb components Eed and Ring1b had been knocked out. Target genes showed small up-regulation in knockout cells but VPA did not further induce transcription. It was concluded that histone acetylation plays an important role in transcription but additional signals are required for transcriptional induction and cellular memory. My results suggest the existence of protective mechanisms against hyperacetylation and highlight the complexity of epigenetic regulation, potentially involving many layers of control.

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7

Ng, Kit. "Epigenetic memory of donor cell differentiation status in Xenopus nuclear transplant embryos." Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.615284.

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VIGORELLI, VERA. "CD34+ stem cells and epigenetic memory: key players and pharmacological targets in diabetic cardiovascular complication." Doctoral thesis, Università degli studi di Pavia, 2020. http://hdl.handle.net/11571/1371994.

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9

Seaborne, R. A. "The role of DNA methylation in the regulation of skeletal muscle atrophy, hypertrophy and epigenetic 'memory'." Thesis, Liverpool John Moores University, 2018. http://researchonline.ljmu.ac.uk/9473/.

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Skeletal muscle mass is vitally important for the maintenance of health and quality of life into old age, with a plethora of disorders and diseases linked to the loss of this tissue. As a consequence, molecular biologists have extensively investigated both atrophying and hypertrophying skeletal muscle, in order to understand the molecular pathways that are induced to evoke both loss and growth of skeletal muscle. Despite huge progressions in the field, a full understanding of the molecular mechanisms that orchestrate growth and loss in skeletal muscle, remain elusive. In this regard, epigenetics, referring to alterations in gene expression via structural modifications of DNA without fundamental alterations of the DNA code, have recently become a promising area of research, specifically for its role in modulating genetic expression. However, the field of skeletal muscle epigenetics is in its infancy, and as such, there is currently a distinct paucity of research investigating this biological phenomenon. Herein, a genomic approach was utilised to examine the role DNA methylation plays in modulating the response, at both a genetic and phenotypic level, of mammalian skeletal muscle. The methodological and analytical approaches utilised in this thesis identify a number of important, novel and impactful findings. Firstly, it is identified that DNA methylation displays a distinct inverse relationship with gene expression during both muscular atrophy and hypertrophy, these findings are furthered by work identifying that DNA methylation alterations may precede functional changes in gene expression during skeletal muscle hypertrophy. This thesis also elucidated that skeletal muscle possesses an epigenetic memory that creates an enhanced adaptive response to resistance load induced hypertrophy, when the same stimulus was previously encountered. Finally, in human subjects, a number of novel and previously unstudied gene transcripts were identified that display significantly positive correlations with changes in skeletal muscle mass, as evoked by resistance training. The data in this thesis demonstrates an important role for DNA methylation in regulating skeletal muscle mass during periods of both muscle atrophy and hypertrophy, respectively. The work presented here may allow for further work to be conducted, expanding our understanding of epigenetics in skeletal muscle and best facilitating the development of therapeutics that may alleviate the detrimental effects observed during periods of skeletal muscle atrophy.

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Wendeln, Ann-Christin [Verfasser]. "Long-lasting epigenetic microglial memory of peripheral inflammation modulates hallmarks of Alzheimer's disease pathology / Ann-Christin Wendeln." Tübingen : Universitätsbibliothek Tübingen, 2020. http://d-nb.info/1217249214/34.

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11

LONGARETTI, ALESSANDRA. "EPIGENETIC HOMEOSTATIC MECHANISM IN NEURONAL ADAPTATION AND METAPLASTICITY TO ENVIRONMENTAL STIMULI." Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/796757.

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It is widely known that environmental stress represents a driving factor for the onset of mental illnesses, common multifactorial disorders that cause a strong deterioration of the quality of life. Upon a stressful event the glutamatergic system is strongly engaged in many brain areas, in particular the hippocampus. Upon acute stress, glutamatergic transmission is boosted in order to promptly respond to the incoming threat and to allow the consolidation of stressful memories to respond to similar future events. However, thanks to homeostatic synaptic plasticity mechanisms devoted to stress coping, no long-term stress-related negative consequences occur. A different scenario is represented by chronic stress. Upon continuous unpredictable series of stresses glutamatergic transmission is altered, since stress-coping mechanisms might fail. This could result, in vulnerable individuals, in the development of neuropsychiatric disorders. The aim of my PhD work was to investigate the function of the epigenetic corepressor LSD1 and of its brain-specific dominant negative isoform neuroLSD1 in the transcriptional mechanisms underlying neuronal plasticity and affecting complex emotional and cognitive behaviors. In particular, I focused on the role of these enzymes in stress response, a process that entails memorization of the traumatic event but that, at the same time, requires homeostatic mechanisms to avoid a too vivid memorization of the stressful event. We hypothesize that the modulation of the ratio of LSD1 isoforms that occurs upon psychosocial stress is implicated in this homeostasis, with the aim of buffering stress response and the consequent memory consolidation of the traumatic event. Through molecular, biochemical, ultrastructural, electrophysiological and behavioral approaches we tried to test this hypothesis. We found that stress-dependent LSD1 isoforms shift towards a repressive layout (increase of LSD1 and decrease of neuroLSD1) is engaged upon NMDAr activation. This is supported by in vitro and in vivo experimental data; indeed blockade of the NMDAr with MK-801 hampers neuroLSD1 downregulation. Thanks to a pharmacological approach that specifically downregulates neuroLSD1, we observed a negative modulation of basal glutamatergic transmission in terms of frequency and amplitude of mEPSCs. Moreover, we found a less responsive post-synaptic density from a biochemical, electrophysiological and structural point of view in neuroLSD1-/- mice. Furthermore, analyzing human hippocampal samples we found that neuroLSD1 decreases along with aging, supporting a role in the negative modulation of memory processes. In parallel, I focused my studies on the endocannabinoid system, another player implicated in this homeostatic process. In particular, I found a crosstalk among LSD1 isoforms and the endocannabinoid system in restraining glutamatergic neuroplasticity in response to stress-induced glutamate release thought the transcriptional repression of ABHD6 and MAGL, the degradative enzymes of the endocannabinoid 2-arachidonyl glycerol. From our data we can conclude that these nuclear and synaptic processes might participate in a converging complex negative feedback mechanism aimed at decreasing stress-induced glutamatergic signaling in the hippocampus, promoting stress termination and possibly the buffering of memory consolidation.

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Conine, Colin C. "Small RNAs and Argonautes Provide a Paternal Epigenetic Memory of Germline Gene Expression to Promote Thermotolerant Male Fertility: A Dissertation." eScholarship@UMMS, 2014. https://escholarship.umassmed.edu/gsbs_diss/724.

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During each life cycle, gametes must preserve and pass on both genetic and epigenetic information, making the germline both immortal and totipotent. In the male germline the dramatic morphological transformation of a germ cell through meiosis, into a sperm competent for fertilization, while retaining this information is an incredible example of cellular differentiation. This process of spermatogenesis is inherently thermosensitive in numerous metazoa ranging from worms to man. Here, I describe the role of two redundant AGO-class paralogs, ALG-3/4, and their small RNA cofactors, in promoting thermotolerant male fertility in Caenorhabditis elegans. alg-3/4 double mutants exhibit temperature dependent sterility resulting from defective spermiogenesis, the postmeiotic differentiation of haploid spermatids into spermatozoa competent for fertilization. The essential Argonaute CSR-1 functions with ALG-3/4 to positively regulate target genes required for spermiogenesis by promoting transcription via a small RNA positive feedback loop. Our findings suggest that ALG-3/4 functions during spermatogenesis to amplify a small-RNA signal loaded into CSR-1 to maintain transcriptionally active chromatin at genes required for spermiogenesis and to provide an epigenetic memory of male-specific gene expression. CSR-1, which is abundant in mature sperm, appears to transmit this memory to offspring. Surprisingly, in addition to small RNAs targeting male-specific genes, we show that males also harbor an extensive repertoire of CSR-1 small RNAs targeting oogenesis-specific mRNAs. The ALG-3/4 small RNA pathway also initiates silencing small RNA signals loaded into WAGO vii Argonautes, which function to posttranscripitonally silence their target mRNAs. Silencing WAGO/small RNA-complexes are present in sperm and presumably transmitted to offspring upon fertilization. Together these findings suggest that C. elegans sperm transmit not only the genome but also epigenetic activating and silencing signals in the form of Argonaute/small-RNA complexes, constituting a memory of gene expression in preceding generations.

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Conine, Colin C. "Small RNAs and Argonautes Provide a Paternal Epigenetic Memory of Germline Gene Expression to Promote Thermotolerant Male Fertility: A Dissertation." eScholarship@UMMS, 2009. http://escholarship.umassmed.edu/gsbs_diss/724.

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During each life cycle, gametes must preserve and pass on both genetic and epigenetic information, making the germline both immortal and totipotent. In the male germline the dramatic morphological transformation of a germ cell through meiosis, into a sperm competent for fertilization, while retaining this information is an incredible example of cellular differentiation. This process of spermatogenesis is inherently thermosensitive in numerous metazoa ranging from worms to man. Here, I describe the role of two redundant AGO-class paralogs, ALG-3/4, and their small RNA cofactors, in promoting thermotolerant male fertility in Caenorhabditis elegans. alg-3/4 double mutants exhibit temperature dependent sterility resulting from defective spermiogenesis, the postmeiotic differentiation of haploid spermatids into spermatozoa competent for fertilization. The essential Argonaute CSR-1 functions with ALG-3/4 to positively regulate target genes required for spermiogenesis by promoting transcription via a small RNA positive feedback loop. Our findings suggest that ALG-3/4 functions during spermatogenesis to amplify a small-RNA signal loaded into CSR-1 to maintain transcriptionally active chromatin at genes required for spermiogenesis and to provide an epigenetic memory of male-specific gene expression. CSR-1, which is abundant in mature sperm, appears to transmit this memory to offspring. Surprisingly, in addition to small RNAs targeting male-specific genes, we show that males also harbor an extensive repertoire of CSR-1 small RNAs targeting oogenesis-specific mRNAs. The ALG-3/4 small RNA pathway also initiates silencing small RNA signals loaded into WAGO vii Argonautes, which function to posttranscripitonally silence their target mRNAs. Silencing WAGO/small RNA-complexes are present in sperm and presumably transmitted to offspring upon fertilization. Together these findings suggest that C. elegans sperm transmit not only the genome but also epigenetic activating and silencing signals in the form of Argonaute/small-RNA complexes, constituting a memory of gene expression in preceding generations.

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Citir, Gozde. "A Study On Cobalt Adaptation And Memory Retention Of Freshwater Bacteria Isolates." Master's thesis, METU, 2010. http://etd.lib.metu.edu.tr/upload/12612824/index.pdf.

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The mucus-dwelling bacteria previously isolated from the surface of a freshwater fish species (Alburnus alburnus from Lake Mogan, Ankara), were studied to discover their cobalt resistance. The minimum inhibitory concentrations (MIC) were determined for a total of thirty six bacterial isolates. The results of the resistance studies led us to design experiments on adaptation to cobalt and subsequent memory retention. Three selected isolates were exposed to an inhibitory cobalt concentration as a mixed culture and individually. The delayed formation of colonies along with competitive exclusion of one of the isolates in the mixed culture were recorded. The delay for colony formation was followed up for liquid culture conditions. After some of our isolates acclimated to cobalt and started to exhibit constant time of growth period, it is assumed that they were adapted. We regarded adaptation as a result of memory formation. Next, we did a further study to find out how long this memory could be retained via serial multiple passages in cobalt free medium. We expressed our observations quantitatively by measuring the growth by using spectrophotometer and by performing viable counts. Interestingly, where there was a high CFU, the photometric values were very low. We interpreted the finding such that the presence of cobalt above tolerance limits were causing size reduction in the cells. So that their presence was underestimated by optic devices in visible range. Our study hinted that freshwater bacteria was adapting cobalt in a memory based mechanism and able to retain this memory for some time.

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Lesburgueres, Edith. "Implication fonctionnelle de l’interface hippocampo-corticale dans le processus de consolidation systémique de la mémoire associative non spatiale chez le rat : contribution du mécanisme d’étiquetage neuronal." Thesis, Bordeaux 1, 2009. http://www.theses.fr/2009BOR13982/document.

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La formation et le stockage à long terme des souvenirs mettent en jeu le processus de consolidation mnésique. S’il est maintenant bien admis que ce processus requiert une interaction entre la formation hippocampique et différentes régions corticales dépositaires des souvenirs, les mécanismes qui sous-tendent ce dialogue restent encore mal connus. En combinant chez le rat des approches comportementale, d’imagerie cellulaire et d’inactivations pharmacologiques des voies de signalisation intracérébrales impliquées dans l’épigenèse, nous avons cherché dans ce travail de thèse à élucider certains des mécanismes responsables de la formation des souvenirs au niveau cortical. Dans la perspective de pouvoir appréhender de façon temporellement précise le dialogue hippocampo-cortical au cours du processus de consolidation à l’échelle systémique, notre premier objectif a été de valider une épreuve comportementale adaptée à l’étude de ce processus, la transmission sociale de préférence alimentaire. Nos résultats ont montré que cette tâche, qui ne nécessite qu’une phase d’acquisition ponctuelle, induit une mémoire robuste et durable. Cette mémoire s’appuie sur des stimuli olfactifs de nature non spatiale. Son caractère associatif nécessite l’implication fonctionnelle de l’hippocampe et de régions corticales spécifiques comme le cortex orbitofrontal qui joue un rôle crucial dans le traitement d’informations de nature olfactive. Dans une deuxième série d’expériences, une approche d’imagerie cellulaire utilisant le facteur de transcription c-fos couplée à une approche pharmacologique d’inactivation transitoire région-spécifique a révélé le rôle crucial du cortex orbitofrontal dans le rappel d’informations anciennes (délai de 30 jours) mais pas récentes (délai de 1 jour). Nous avons par ailleurs mis en évidence que la consolidation des informations dans cette structure s’accompagnait de changements progressifs de l’architecture des réseaux neuronaux comme la formation de nouvelles synapses (synaptogénèse) ou l’augmentation du nombre d’épines dendritiques. En accord avec le modèle standard de la consolidation mnésique, ce recrutement cortical était associé à un désengagement de l’hippocampe, confirmant le rôle transitoire de cette structure dans le rappel à long terme d’informations olfactives associatives. Dans une troisième série d’expériences, nous nous sommes intéressés aux mécanismes pouvant sous-tendre l’établissement de la mémoire à long terme au niveau cortical. Nos résultats apportent un éclairage nouveau sur la dynamique des interactions hippocampo-corticales pendant la consolidation systémique en démontrant la nécessité d’un étiquetage des assemblées neuronales du cortex orbitofrontal dès l’encodage des informations. Un blocage de cet étiquetage par une inactivation de ce cortex au moment de l’interaction sociale (phase d’acquisition) a perturbé le rappel à long terme et empêché les modifications de l’architecture des réseaux neuronaux corticaux normalement associés au stockage à long terme des informations olfactives. Sur le plan cellulaire, cet étiquetage requiert l’activation des récepteurs NMDA et de la voie des MAPK, ainsi que l’acétylation des protéines histones impliquées dans la régulation de l’état transcriptionnel de la chromatine. En modifiant leur état d’acétylation, nous avons pu moduler positivement ou négativement le rappel à long terme des informations olfactives relatives à la préférence alimentaire. Ainsi, nos données soulignent l’importance du dialogue hippocampo-cortical dans l’établissement de la mémoire à long terme
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Carrasco, Wong Ivo [Verfasser], and Paola [Akademischer Betreuer] Casanello. "Oxidative stress-induced epigenetic transcriptional memory as a mechanism of programmed endothelial dysfunction in large for gestational age newborn of women with obesity / Ivo Carrasco Wong ; Betreuer: Paola Casanello." Regensburg : Universitätsbibliothek Regensburg, 2019. http://d-nb.info/118990537X/34.

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Lizotte, Farah. "Mémoire hyperglycémique dans la néphropathie diabétique : implication potentielle de SHP-1." Mémoire, Université de Sherbrooke, 2015. http://hdl.handle.net/11143/6980.

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Résumé : La néphropathie diabétique (ND) est une complication microvasculaire du diabète évoluant ultimement en insuffisance rénale et l’hyperglycémie est connue comme étant l’un des facteurs de risques. De larges études cliniques, tel que le DCCT et l’UKPDS, ont montré que si le contrôle intensif de la glycémie se faisait de façon précoce, il serait possible de retarder le développement de la ND. Cependant, les résultats de l'EDIC montrent que si ce contrôle intensif se faisait plus tardivement, suite à une période d’hyperglycémie, il n’empêcherait plus sa progression. Les podocytes ont un rôle critique dans le maintien des fonctions rénales et leur apoptose corrèle de façon très spécifique avec la progression de la ND. Récemment, nous avons rapporté que SHP-1, une protéine tyrosine phosphatase, était augmentée en concentrations élevées de glucose (HG), menant à une inhibition des voies de signalisation de l'insuline. Notre hypothèse est que l’augmentation de l’expression de SHP-1 causée par l’hyperglycémie persiste même après réduction des niveaux de glucose, phénomène de mémoire hyperglycémique, causant une résistance à l'insuline, la mort des podocytes et une absence de réversibilité liée à la progression de ND. Les résultats in vivo montrent que la fonction et la pathologie rénale continuent de progresser et ce en dépit de la normalisation des niveaux de glucose avec implants d’insuline de 5 à 7 mois d’âge La progression de la pathologie corrèle avec le maintien de l’augmentation de l’expression de SHP-1, contribuant au maintien de l’inhibition des voies de l’insuline. En culture, des podocytes murins exposés en HG pendant 96 h et ensuite exposés en condition normale de glucose(NG) pour les dernières 24 h montrent une persistance de l’inhibition des voies de signalisation de l’insuline qui corrèle avec l’augmentation persistante de l’expression et l’activité phosphatase de SHP-1. L’activité des caspases 3/7 dans les podocytes est plus élevée lorsque ceux-ci sont exposés en HG qu’en NG. Le retour en NG pour les dernières 24 h n’a aucun effet bénéfique à réduire l’activité des caspases 3/7. Finalement, l’analyse épigénétique a été suggérée comme étant une explication du phénomène de mémoire hyperglycémique. La monométhylation de la lysine 4 de l’histone 3 (H3K4me1), un marqueur d’activation génique, est augmentée sur le promoteur de SHP-1 en HG et demeure élevée malgré le retour en NG pendant les dernières 24 h. En conclusion, l’hyperglycémie engendre une augmentation persistante de SHP-1 due possiblement à des modifications épigénétiques, causant le maintien de l’inhibition les voies de signalisation de l’insuline même après un retour à des niveaux normaux de glucose, contribuant à la progression de la ND.
Abstract : Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Renal podocytes apoptosis induced by hyperglycemia is an early event of DN. Clinical studies have shown that intensive blood glucose control reduced the development of DN but is not sufficient, if started late, to prevent its progression, introducing the concept of “hyperglycemic memory”. We have recently published that the tyrosine phosphatase SHP-1 is elevated in renal cortex of type 1 diabetic mice (Akita), contributing to insulin unresponsiveness and DN. We hypothesized that SHP-1 expression remains elevated regardless of systemic blood glucose normalization, and is responsible for hyperglycemic memory in podocytes leading to DN progression. In vivo contribution of SHP-1 in hyperglycemic memory was evaluated using Akita mice treated with insulin implants after 4 months of diabetes. Both urinary albuminuria and glomerular filtration rate were significantly increased in diabetic mice compared to non-diabetic mice and remained elevated despite normalization of blood glucose levels. Renal dysfunction was associated with a persistent increase of SHP-1 expression in renal cortex and inhibition of insulin action that were not normalized following insulin implants. Mouse podocytes were cultured in normal (5.6mM; NG), high glucose concentrations (25mM; HG) for 120 h or HG (96 h) followed by NG for an additional 24 h (HG+NG). We observed that Akt and ERK phosphorylation induced by insulin was inhibited in HG and were not restored despite returning glucose level to 5.6 mM after the HG period. This inhibition was associated with persistent increase of SHP-1 expression and phosphatase activity, leading to insulin signaling pathway inhibition. Moreover, caspase 3/7 activity in podocytes exposed to HG was higher than in podocytes cultured in NG and returning glucose concentrations to normal range for the last 24 h after the 96 h HG exposure had no effect on reducing caspase 3/7 activity. Epigenetic changes were studied to explain the hyperglycemic memory effect. On SHP-1 promoter, H3K4me1 levels, an activation mark, tended to be more elevated in podocytes exposed to HG and were maintained despite returning to NG levels after the HG conditions. In conclusion, hyperglycemia induces persistent and epigenetic changes of SHP-1 causing insulin unresponsiveness in the podocytes contributing to DN progression.

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Fontoura, Tamiris Schaeffer. "Avaliação transgeracional dos efeitos da dieta hipercalórica sobre o metabolismo e cognição em ratos." Universidade Federal de Juiz de Fora (UFJF), 2017. https://repositorio.ufjf.br/jspui/handle/ufjf/5665.

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A obesidade é um distúrbio multifatorial complexo causada por fatores genéticos e epigenéticos, dentre outros. Um meio intra-uterino adverso, com excesso ou escassez de alimentos pode expor o feto ao desenvolvimento da síndrome metabólica, diabetes e doenças cardiovasculares quando adultos, podendo ser passado transgeracionalmente através de alterações epigenéticas. O exercício físico é uma forma não medicamentosa de prevenção e tratamento da obesidade, melhorando a aptidão cardiorrespiratória e composição corporal, dentre outros fatores. Este estudo avaliou se a dieta rica em sacarose e lipídios dada a fêmeas da geração F0 durante toda sua vida, incluindo gestação e lactação, afetaria os níveis de ansiedade e os padrões de memória transgeracionalmente e se o exercício físico possui efeito protetor sobre os mesmos parâmetros. Ratas da geração F0 foram distribuídas em quatro grupos: controle sedentário (CSed) e exercitado (CEx); dieta sedentário (DSed) e exercitado (DEx). Dos 21 aos 120 dias de vida os animais realizaram treinamento físico em esteira, com intensidade de moderada a intensa, e os animais controle receberam dieta normocalórica e os animais dieta receberam a dieta high sugar/ high fat (HS/HF) no mesmo período. Machos e fêmeas da geração F1 e F2 foram distribuídos em grupos iguais ao da geração materna ao qual pertenciam; porém, consumiram a ração normocalórica e não realizaram treinamento físico. Foi acompanhado o consumo alimentar dos animais e a evolução do peso corporal dos mesmos. Aos 80 dias, foi realizado teste oral de tolerância à glicose (TOTG). Aos 90 dias, todos os animais foram submetidos a testes, para avaliação do nível de ansiedade (labirinto em cruz elevado) memórias de trabalho (30 seg) e longo prazo (24h) (teste de esquiva inibitória). Aos 110 dias, houve a eutanásia e os parâmetros biométricos foram avaliados. A dieta normocalórica e o treinamento físico realizado pela geração F0 promoveram menor acúmulo de gordura nos filhotes machos e fêmeas da geração F1 quando comparados ao CSed1 (gordura retroperitonial: 37,7% nas fêmeas e 27,6% nos machos; gordura perigonadal: 28,16% nos machos). Diferentemente do que aconteceu na geração F1, os machos do grupo DSed2 apresentaram um maior acúmulo de gordura perigonadal, 19,4%, quando comparados ao grupo Csed2. Adicionalmente, o efeito protetor do treinamento físico com relação ao menor acúmulo de gorduras retroperitoniais e perigonadais na geração F2 só aconteceu no grupo DEx2 e nos machos, com redução de 21% e 26,8%, respectivamente, em relação ao grupo DSed2. As fêmeas dos grupos DSed das gerações F1 e F2 não ficaram intolerantes a glicose, contudo houve redução de 11,2% na glicemia das fêmeas do grupo DEx1 quando comparadas ao grupo DSed1. Ao contrário do que aconteceu nas fêmeas da primeira geração, os machos do grupo DSed1 ficaram intolerantes a glicose, com aumento da glicemia em 18,45% quando comparados ao grupo CSed1. O grupo DEx1 e DEx2 apresentaram redução da glicemia em 18,45% e 24,75% quando comparados ao grupo DSed. A dieta HS/HF consumida pela geração F0 reduziu a memória de longo prazo das fêmeas do grupo DSed2 em 88,6% quando comparadas ao grupo CSed2. Também aumentou os níveis de ansiedade dos animais machos da geração F1 do grupo DSed1 em relação aos grupos CSed1 e DEx1. A dieta HS/HF aumentou o nível de ansiedade dos machos da geração F1 e causou prejuízo na memória de longo prazo das fêmeas da geração F2, além de aumentar a glicemia dos filhotes machos do grupo dieta da primeira geração e, causar maior acúmulo de gordura na geração F2. O treinamento físico teve efeito protetor sobre a glicemia da descendência, reduziu a adiposidade dos filhotes machos e fêmeas de F1 (grupo controle). Tal efeito só se manteve na geração F2 nos filhotes machos do grupo dieta. A dieta HS/HF consumida por fêmeas desde o desmame até a lactação altera o metabolismo, a memória e os níveis de ansiedade nas gerações F1 e F2, particularmente entre os machos. O treinamento físico de intensidade moderada a intensa realizada pela geração F0 protege a progênie.
Obesity is a complex multifactorial disorder caused by genetic and epigenetic factors, among others. An adverse intrauterine environment with excess or scarcity of food may expose the fetus to the development of metabolic syndrome, diabetes, and cardiovascular disease in adults, and may be transgenerationally passed through epigenetic changes. Physical exercise is a non-medicated form of prevention and treatment of obesity, improving cardiorespiratory fitness and body composition, among other factors. This study evaluated whether the diet rich in sucrose and lipids given to females of the F0 generation throughout their life, including gestation and lactation, would affect anxiety levels and memory patterns transgenerationally and if physical exercise has protective effect on the same parameters. Rats of the F0 generation were divided into four groups: sedentary (CSed) and exercised (CEx) controls; Sedentary (DSed) and exercise diet (DEx). From 21 to 120 days of age, the animals performed physical training on a treadmill at moderate to high intensity, and the control animals received normocaloric diet and the diet animals received the high sugar / high fat (HS / HF) diet during the same period. Males and females of the F1 and F2 generation were distributed in equalgroupsl to the maternal generation to which they belonged; however, consumed the normocaloric chow and did not perform physical training. The food consumption of the animals and their body weight were monitored. At 80 days, oral glucose tolerance test (OGTT) was performed. At 90 days, all animals were submitted to tests, for evaluation of anxiety level(elevated plus-maze) working memory (30 sec) and long-term (24h) (inhibitory avoidance test). At 110 days, there was euthanasia and the biometric parameters were evaluated. The normocaloric diet and physical training performed by the F0 generation promoted a lower accumulation of fat in the offspring, male and female from F1 generation, compared to CSed1 (retroperitoneal fat: 37.7% in females and 27.6% in males, perigonadal fat 28.16%, in males). Differently from what happened in the F1generation, the males of the DSed2 group presented a higher accumulation of perigonadal fat, 19.4%, when compared to the group Csed2. Additionally, the protective effect of physical training in relation to the lower accumulation of retroperitoneal and perigonadal fats in the F2 generation occurred only in the DEx2 group and in the males, with a reduction of 21% and 26.8%, respectively, in relation to the DSed2 group. Females of the DSed groups of the F1 and F2 generations were not intolerant to glucose, however, there was a 11.2% reduction in the glycemia of the females of the DEx1 group when compared to the DSed1 group. In contrast to what happened in the first-generation females, males from the DSed1 group were intolerant to glucose, with an increase in blood glucose by 18.45% when compared to the CSed1 group. The group DEx1 and DEx2 had a reduction in blood glucose of 18.45% and 24.75% when compared to the DSed group. The HS / HF diet consumed by the F0 generation reduced the long-term memory of the females of the DSed2 group by 88.6% when compared to the CSed2 group. It also increased the anxiety levels of male F1 generation from the DSed1 group in relation to the CSed1 and DEx1 groups. The HS / HF diet increased the anxiety level of the F1 generation males and caused long-term memory injury in females of the F2 generation, in addition to increasing the glycemia of the first-generation diet group males and causing higher fat accumulation In the F2 generation. Physical training had a protective effect on offspring glycemia, reducing the adiposity of male and female F1 pups (control group). This effect was only maintained in the F2 generation in the male offspring of the diet group. The HS / HF diet consumed by females from weaning to lactation alters metabolism, memory and anxiety levels in the F1 and F2 generations, particularly among males. Physical training of moderate to intense intensity performed by the F0 generation protects the progeny.

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Bouarab, Chloe. "Modifications post-traductionnelles des histones au sein du circuit hippocampo-amygdalien déterminant le passage d'une mémoire de peur normale à une mémoire traumatique." Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0261/document.

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Les altérations mnésiques associées au trouble de stress post-traumatique (TSPT) constituent un aspect fondamental de la symptomatologie de cette pathologie. Cette altération qualitative de la mémoire inclut à la fois une hypermnésie, c’est-à-dire une intensification de la mémoire vis-à-vis du coeur de l’événement traumatique, et une amnésie de type déclaratif pour les éléments contextuels péri-traumatiques. Les données chez l’Homme suggèrent que ces altérations mnésiques pourraient être sous-tendues par une hyper-activation amygdalienne et un dysfonctionnement hippocampique, respectivement. Cependant, les bases neurobiologiques, et en particulier moléculaires, du TSPT restent largement méconnues. Un modèle comportemental développé chez la souris au laboratoire et basé sur un conditionnement aversif permet précisément de comparer une mémoire de peur normale, c’est-à-dire « contextualisée » et adaptée, à une mémoire pathologique de type TSPT, c’est-à-dire « décontextualisée » et focalisée sur un élément saillant du trauma. Dans la mesure où il a été montré que le développement d’une mémoire de peur contextuelle implique certaines modifications épigénétiques spécifiques, nos travaux ont eu pour objectif de déterminer les altérations des modifications post-traductionnelles d’histones qui sous-tendent le développement d’une mémoire traumatique au lieu d’une mémoire de peur normale. Nos résultats révèlent (1) que des profils spécifiques différents des états d’acétylation/méthylation de l’histone H3 dans le réseau hippocampo-amygdalien sont associés à une mémoire de peur normale et à une mémoire traumatique de type TSPT. Spécifiquement, une mémoire de peur normale est associée à une forte acétylation de H3K9 hippocampique, tandis qu’une mémoire traumatique de type TSPT s’accompagne d’une hyperméthylation de H3K9 dans l’hippocampe, traduisant une répression transcriptionnelle, ainsi que d’une diminution de la tri-méthylation de H3K27 dans l’amygdale latérale, caractéristique d’une activation transcriptionnelle. De plus, nos travaux montrent (2) qu’une modulation pharmacologique de la balance des états d’acétylation/méthylation de H3K9 dans l’hippocampe permet de promouvoir ou de prévenir le développement d’une mémoire traumatique. Enfin, (3) une dernière série d’expériences révèle (i) qu’un stress prénatal est un facteur de risque au développement d’une mémoire traumatique, (ii) que cette dernière est associée à des profils épigénétiques spécifiques, et (iii) qu’une telle vulnérabilité peut se transmettre de manière intergénérationnelle
Memory alterations associated with post-traumatic stress disorder (PTSD) are a fundamental feature of this pathology. PTSD is characterized both by hypermnesia for simple salient trauma-related stimuli and amnesia for peri-traumatic contextual cues. In humans, this disorder is associated with hippocampal hypofunction and amygdalar hyperfunction, which may underlie such paradoxical memory pattern. However, neurobiological bases of PTSD, particularly at the molecular level, remain largely unknown. A behavioral model based on aversive conditioning was developed in mice by our team. This model allows the comparison between a normal, i.e. “contextualized” and adaptive, fear memory, and a PTSD-like pathological fear memory, i.e. “decontextualized” and focused on a salient cue of the trauma. Since specific epigenetic alterations have been involved in the development of contextual fear memory, our aim was the identification of the alterations in post-translational histone modifications underlying the development of traumatic memory instead of normal fear memory. Our results first reveal that normal and PTSD-like fear memory are associated with distinct acetylation/methylation profiles of histone H3 in the hippocampal-amygdalar network. Specifically, we show that, compared to normal fear memory, PTSD-like memory is associated with a switch from H3K9 hyperacetylation (marker of transcriptional activation) to H3K9 hypermethylation (marker of transcriptional repression) in hippocampal CA1, as well as a significant reduction of H3K27 trimethylation, which results in an increased transcription, in the lateral amygdala. Second, we show that the pharmacological manipulation of the acetylation/methylation balance of H3K9 in the hippocampus can prevent or promote the development of PTSD-like memory. Finally, a last series of experiments shows that (i) prenatal stress is a risk factor for the development of PTSD-like memory, (ii) which is associated with specific epigenetic alterations and (iii) that such vulnerability to stress can be transmitted to subsequent generations

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Rabiei, Far Parisa. "Differential gene expression profiling of chromatin-modifying enzymes and remodeling factors in the rat motor cortex after motor skill training." Thesis, Örebro universitet, Institutionen för naturvetenskap och teknik, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-28572.

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Fine motor skills are learned through repetitive practice and once learned, last for a long time. Skilled reaching is linked to structural and functional changes in multiple brain regions including, in particular, the primary motor cortex. Previous studies demonstrated that fine motor skill learning is associated with cortical synaptogenesis and motor map reorganization. At present, studies have implicated an indispensable role of epigenetic alterations in both hippocampal- and striatal-dependent memory formations, while examinations into the epigenetic changes in the primary motor cortex are lacking. The current study was aimed to identify epigenetic changes in motor cortex as a result of extensive motor skill learning using the single pellet skilled reaching task. Male Wistar rats were trained in the single pellet skilled reaching task (n = 6) for 10 consecutive days or were, under similar conditions, given access to pellets that did not require skilled reaches (n = 6). Skilled motor trained rats exhibited a rapid increase in successful reaches during the first four days of motor training before reaching a plateau, indicative of the acquisition and consolidation of the learned task, respectively. Expression proﬁles of chromatin modifying enzymes were screened using epigenetic-targeted PCR arrays. Results suggest that gene expression levels of multiple chromatin regulatory enzymes were down-regulated in the motor cortex of trained animals compared to controls following 10 days of motor training in the skilled reaching task. Among the chromatin modifying enzymes, the transcription level of Smyd1 (SET and MYND domain containing 1; NM_001106595) was lower (-2.17 fold-change) in motor cortex after 10 days of training compared to controls. Our results point to an epigenetic regulation of chromatin modification markers in the primary motor cortex that possibly underlie the mechanisms of synaptic plasticity, synaptogenesis and the formation of procedural memory.

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Istaces, Nicolas. "Transcriptional control of innate memory CD8+ T cells." Doctoral thesis, Universite Libre de Bruxelles, 2019. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/295204.

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CD8+ T cells are essential for host protection against intracellular pathogens and tumors. During antigen-driven responses, CD8+ T cell fate is governed by transcriptional and epigenetic processes that allow naïve CD8+ T cells to develop into a wide range of effector and conventional memory cell subsets. Over the last decades, novel techniques and major efforts led to a better understanding of the origin, nature, and short- and long-term effects of these processes on individual CD8+ T cells. Under certain conditions, naïve CD8+ T cells can acquire memory phenotype and functions in an antigen-independent manner. Although homeostatic cytokines and initial activation pathways that drive the development of these unconventional memory cells had been identified, the ensuing transcriptional profile of these cells and their degree of similarity with conventional memory cells remained ill-defined. The epigenetic events that accompany unconventional memory formation were also not known.Here, we show that innate memory cells, a type of thymic unconventional memory cells, are transcriptionally close to conventional memory cells but only partially epigenetically programmed toward the full memory fate. We also show that the sole overexpression of the transcription factor Eomesodermin (EOMES), a master regulator of effector and conventional memory cells, is able to drive many of the phenotypical, functional, transcriptional, and epigenetic features of innate memory cells, and to induce the recruitment of BRG1, a member of chromatin remodeling complexes, to innate memory gene regulatory regions. We further show that the in vivo interleukine-4-dependent development of innate memory cells is largely dependent on BRG1. We bring to light that, in innate memory cells, EOMES is recruited in many instances to genomic regions previously bound by the transcription factor RUNX3. Overall, we provide insights into the mechanisms that allow memory cell formation and T cell receptor stimulation to be uncoupled.
Doctorat en Sciences médicales (Médecine)
info:eu-repo/semantics/nonPublished

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Eymard, Eric D. "Role of ETS-1 and Histone Methylation Patterns in Rapid Recall Ability of Memory T Cells." University of Cincinnati / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1613744260170862.

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Cassel, Raphaelle. "Impact de la réactivation de l'acétylation des histones sur les performances mnésiques dans un modèle transgénique murin de la maladie d'Alzheimer : vers une nouvelle stratégie thérapeutique ?" Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ040/document.

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La maladie d’Alzheimer (MA) est caractérisée par une perte progressive des capacités mnésiques et des fonctions cognitives accompagnée du développement de dégénérescences neurofibrillaires (DNFs) et de plaque séniles dans le parenchyme cérébral. La découverte de perturbations épigénétiques dans des cerveaux de patients Alzheimer ont mené la communauté scientifique à se tourner vers de nouvelles voies thérapeutiques. De telles altérations, notamment au niveau de l’acétylation des histones de la chromatine, pourraient rendre compte de dysfonctionnements dans l’expression des programmes génétiques. En utilisant les souris THY-Tau22 (développement progressif de DNFs), nous avons évalué l’efficacité de deux stratégies visant à augmenter l’acétylation des histones : activer les HATs et inhiber les HDACs. Ces deux stratégies permettent une récupération des performances en mémoire spatiale chez les souris THY-Tau22, ouvrant ainsi de nouveaux axes thérapeutiques et de recherches dans la MA
Alzheimer’s disease (AD) is characterized by a progressive loss of memory and cognitive functions associated with the development of neurofibrillary tangles (NFTs) and amyloid plaques in the brain. Nowadays, there is no satisfactory cure for AD. The discovery of epigenetic alterations in AD brain led the scientist community to think about new therapeutic options. Such modifications, and notably those on histone acetylation of the chromatin, could be associated with the genetic dysfunctions observed in AD. The reestablishment of proper epigenetic regulations, and thus gene expression, appears as an original therapeutic option. Using THY-Tau22 mice, we assessed the effect of two strategies aimed at increasing histone acetylation with a HAT activator (CSP-TTK21) or an HDAC inhibitor (phenylbutyrate). We show that both therapeutic strategies allow the rescue of spatial memory performances in the THY-Tau22 mouse model. These results open new leads for AD therapeutics and research

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Gully, Kay. "The plant immune system : induction, memory and de-priming of defense responses by endogenous, exogenous and synthetic elicitors." Thesis, Angers, 2019. http://www.theses.fr/2019ANGE0001/document.

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En tant qu’organismes sessiles, les plantes doivent réagir rapidement et intensément, via des réponses défensives, pour repousser les pathogènes invasifs. Le système immunitaire des plantes peut être déclenché par des molécules élicitrices exogènes ou endogènes. Une autre classe d’éliciteurs, les éliciteurs synthétiques, contient également des composés promouvant une réponse défensive.Dans ce manuscrit, je décris la découverte et caractérisation d’une nouvelle famille de petits peptides endogènes potentiellement sécrétés(PROSCOOP), dont les membres incluent de petits peptides (SCOOP). Je démontre que les SCOOP sont impliqués dans les mécanismes de défense de la plante et le développement racinaire. Une variété de peptides SCOOP induit des réponses défensives de courtes et longues durées.De plus, des traitements avec le peptideSCOOP12 induisent une résistance à Pseudomonas syringae chez Arabidopsis.Dans la seconde partie de cette thèse, je démontre que le traitement des plantes avec un éliciteur synthétique peut mener à une mémoire transcriptionnelle à long terme, et que le challenge subséquent des plantes traitées par application d’un éliciteur exogène désactive cette mémoire transcriptionnelle. En conclusion, ma thèse présente (1) la diversité des fonctions que peuvent avoir ces éliciteurs et (2) l’impact sur les systèmes de défense de la plante et ses conséquences sur la mémoire et le développement de la plante
As sessile organism, plants have to react quickly and strongly with defense responses to repel any invading pathogen. The plant immune system can be triggered by exogenous or endogenous elicitor molecules. Another class of elicitors are defense promoting compounds which are also known as synthetic elicitors. Here I describe the discovery and characterization of a novel family of potentially secreted small endogenous peptides (PROSCOOP) which members harbor small peptides (SCOOPs). I show that the SCOOP family is involved in plant defense and root development. Various SCOOP peptides induce short- and long-term defense responses. Moreover, treatments with the SCOOP12 peptide induce the resistance against Pseudomonas syringae in Arabidopsis. In the second part of this thesis, I show that treatments with a synthetic elicitor can lead to long-term transcriptional memory and that subsequent challenging of such plants with an exogenous elicitor reverted this transcriptional memory. In conclusion, my thesis shows (1) how diverse the function of these elicitors can be and (2) the impact the plant defense system and its triggers have on plant development and memory

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Chatterjee, Snehajyoti. "Role of lysine acetyltransferase (KAT) activation in spatial memory : a new therapeutic approach for memory related disorders such as Alzheimer’s disease." Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ092/document.

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La CREB Binding Protein (CBP) a une activité lysine acétyltransférase intrinsèque et fonctionne aussi comme un co-activateur transcriptionnel. L'activité acétyltransférase et la fonction de coactivateur transcriptionel sont toutes deux essentielles pour la formation de mémoire à long terme. De plus, la dérégulation de CBP a été observée dans des maladies neurodégénératives comme la maladie d'Alzheimer et la maladie de Huntington. L'objectif de ma thèse était d'étudier le rôle de la CBP et de son activation pharmacologique dans le cadre de la formation de la mémoire spatiale, une forme de mémoire qui est démantelé très tôt dans la MA. Les données obtenues à partir de ma thèse montrent que l'activation de la fonction acétyltransférase CBP par l’activateur CSP-TTK21 améliore les processus mnésiques chez des souris adultes normales et aussi dans un modèle murin de MA (THY-Tau22). Ainsi, la stratégie d’activation pharmacologique de l'activité acétyltransférase de CBP a un énorme potentiel pour une utilisation en tant qu'agent thérapeutique pour le traitement des maladies liées à l'altération de la mémoire tel que la maladie d'Alzheimer
CREB Binding Protein (CBP) has an intrinsic lysine acetyltransferase activity and alsofunctions as a transcriptional co-activator. Both the acetyltransferase activity and the transcriptional co-activator function are critical for long-term memory formation. Importantly, CBP dysregulation has been observed in neurodegenerative conditions like in Alzheimer’s disease and Huntington’s disease. The focus of my thesis was to study the role of CBP and its activation by a new pharmacological tool, in the context of spatial memory formation, a form of memory that is very early dismantled in AD. Data obtained from my thesis clearly suggests that activation of CBP acetyltransferase function by small molecule activator CSP-TTK21 can improve memory related processes in healthy adult mice and also in a mouse model of AD, (THY-Tau22). Therefore, the strategy of pharmacological activation of CBP acetyltransferase activity has tremendous potential for use as therapeutics for the treatment of diseases related to memory impairment such as Alzheimer’s disease

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Petsophonsakul, Petnoi. "Hippocampal plasticity underlying learning and memory processes in healthy and diseased conditions." Thesis, Toulouse 3, 2017. http://www.theses.fr/2017TOU30009.

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Les expériences qui jalonnent la vie favorisent la survenue de modifications cérébrales durables et pouvant impacter les fonctions cognitives, ainsi que le développement de troubles cérébraux. L'hippocampe est une structure cérébrale qui joue un rôle essentiel dans l'apprentissage et la mémoire. Dans la première étude, nous avons montré comment l'activité neuronale sous-tendant les processus de la mémoire influence fortement l'intégration des nouveaux neurones hippocampiques dans le cerveau adulte, suggérant une modulation durable de la fonction hippocampique. Dans la deuxième étude, nous avons montré que le séjour en milieu enrichi qui prévient les déficits mnésiques liés à l'âge et induit également des modifications épigénétiques dans le cerveau sain et modèle de la maladie d'Alzheimer. Ceci suggére que des règulations épigénétiques durables pourraient soutenir les effets promnésiques de l'enrichissement environnemental. Ainsi, cette thèse a mis en évidence dans l'hippocampe, l'existence de plasticité dépendante de l'activité dans le cerveau sain et modèle de la maladie d'Alzheimer. Cette plasticité pourrait être une cible pertinente dans le traitement de certaines conditions pathologiques
Throughout life, environmental challenges promote long-lasting changes within the brain that can affect cognitive function, as well as the development of brain disorders. Within the brain, the hippocampus plays a key role in learning and memory processes. In the first study, we demonstrate how neuronal activity triggered by the learning and memory enhances the synaptic integration of adult-born hippocampal neurons that could support hippocampal function. In the second study, we show that enriched environment prevents age-related memory deficits and induces epigenetic modifications in both healthy and Alzheimer's disease conditions. This suggests that long-lasting epigenetic regulations may participate in sustaining the promnesic effects of environmental enrichment. Altogether, this thesis provides evidence of activity-dependent plasticity in the hippocampus in healthy and diseased brain, and suggests that stimulating such plasticity may contribute to improve pathological conditions

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Blank, Martina. "Regulação epigenética na formação da memória aversiva : modulação via inibidores de histona desacetilases." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/119754.

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O estado da cromatina influencia diretamente nos processos de expressão gênica desencadeada durante a formação de memórias. Nesse sentido sendo de grande interesse seu estudo na área biomédica. Modificações epigenéticas como a metilação do DNA e modificações pós-traducionais em histonas são reguladores cruciais do estado da cromatina e ds transcrição gênica. Uma das modificações pós-traducionais mais bem estudada é a acetilação de histonas. Quando as histonas estão acetiladas a cromatina encontra-se num estado relaxado permitindo a expressão gênica. A reação é catalisada por acetiltransferases de histonas (HATs) e é um processo reversível catalisado por histona desacetilases (HDACs). A utilização de fármacos inibidores de histona desacetilases (HDACis) tem ajudado na elucidação dos mecanismos gênicos envolvidos na formação do aprendizado e da memória. Nosso trabalho se baseia na hipótese de que a atividade de HDACs é crucial para modulação das respostas de aprendizado na tarefa de esquiva inibitória e que a acetilação de histonas é um passo essencial neste processo. Os resultados apresentados neste trabalho demonstram que a infusão intra-hipocampal de tricostatina A (TSA) ou butirato sódico (NaB) imediatamente após o treino resulta na melhora da memória de longa duração (LTM). TSA demonstrou ainda possuir duas ondas de efeitos melhoradores da LTM, uma imediatamente e outra 3h após o treino que coincidem com as ondas de ativação de vias de sinalização intracelular e de síntese de proteínas importantes para a formação da LTM. Adicionalmente, a inativação farmacológica da amigdala basolateral (BLA) antes do treino bloqueou os efeitos melhoradores do TSA administrado no hipocampo, evidenciando que a integridade da BLA é importante para este processo. Neste trabalho demonstramos também que a administração intraperitoneal de NaB imediatamente após o treino em animais velhos sem prejuízo cognitivo resulta em melhora significativa da memória. O tratamento com NaB não afetou a LTM de animais jovens saudáveis. Por fim, nossos dados demonstram que a administração de um fármaco antagonista de receptores TrkB, ANA-12, no hipocampo de animais jovens após o treino ou teste resulta no prejuízo da memória. No entanto a administração de NaB antes do treino preveniu os efeitos prejudiciais de ANA-12. Em conjunto estes resultados demonstram que a modulação epigenética através da atividade de HDACs é importante para a formação da LTM. Nossos dados fortalecem ainda a visão de que eventos epigenéticos possuem papel critico no aprendizado e memória interagindo com vias de sinalização intracelulares desencadeadas por estes processos.
The chromatin state directly impacts gene expression triggered by memory formation. Therefore, this process is of great interest to the biomedical area. Critical regulators of chromatin state and gene transcription are the epigenetic modifications such as DNA methylation and posttranslational modifications of histone proteins. One of the most studied postranslational modification of histones is histone acetylation. When histones are acetylated, chromatin is in a relaxed conformation allowing gene expression. Lysine acetylation is catalyzed by histone acetyltransferases (HATs) and is reversed by the action of histone deacetylases (HDACs). The use of histone deacetylase inhibitors (HDACis) is helping to elucidate genetic mechanisms of learning and memory. Our work is based on the hypothesis that HDACs activity is crucial for inhibitory avoidance (IA) learning responses modulation and the idea that histone acetylation is an essential step. The data presented in this work demonstrate that infusion of Trichostatin A (TSA) or Sodium Butyrate (NaB) intrahipocampally produced memory enhancement. Moreover, TSA showed two waves of memory enhancing effects when given immediately or 3 h after training coinciding with the observed waves of protein synthesis and PKA activation for memory formation. Our study also demonstrates that the enhancement of IA memory consolidation depends on the integrity of basolateral amygdala (BLA) since its functional inactivation by muscimol (MUS) completely blocked the enhancing effect of TSA infused in the rat hippocampus. Here, we also demonstrate that intraperitoneal administration of NaB immediately after training led to memory enhancement in aged rats with no cognitive deficit. Surprisingly, NaB had no effect in younger rats with normal memory retention. Finally, data presented here also demonstrate that TrkB activity in the hippocampus is crucial for long-term memory (LTM) since administration of a TrkB receptor antagonist, ANA-12, in the dorsal hippocampus immediately after training or retrieval led to memory retention impairment. Moreover, infusion of NaB before training prevented this impairing effect of TrkB antagonism. Taken together, these results show that epigenetic modulation by HDACs activity is required for memory formation. Our data also supports the idea of HDACs playing critical roles in learning and memory interacting with intracellular signaling pathways triggered by these processes.

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Valiati, Fernanda Endler. "Papel das histonas deacetilases na amígdala basolateral na modulação da memória emocional." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/143055.

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Introdução: A formação da memória envolve mudanças na expressão de genes neuronais. Remodelações epigenéticas da cromatina e modificações pós-traducionais reversíveis no DNA ou nas proteínas histonas representam mecanismos centrais na regulação da expressão gênica durante o desenvolvimento do cérebro e a aprendizagem inicial ou recuperação da memória. Desequilíbrios nos níveis de acetilação de histonas estão associados à uma ampla variedade de desordens cerebrais. Histonas deacetilases (HDACs) desempenham um papel fundamental na homeostase da acetilação de histonas e na regulação de atividades celulares fundamentais como a transcrição, tornando-as um foco de estudo. Evidências mostram que a administração de inibidores de histonas deacetilases (HDACis) restauram a memória associada à regulação da expressão gênica e melhora a memória em ratos. Estudos em modelos animais têm mostrado que a formação da memória envolve uma série de alterações bioquímicas em várias áreas do sistema nervoso central, entre as quais se destacam o hipocampo e a amígdala basolateral (BLA). Neste contexto, fármacos experimentais, como a tricostatina A (TSA), que atuam sobre mecanismos epigenéticos, têm sido recentemente propostos como potenciais terapias para o tratamento de disfunção cognitiva e memória associados a doenças neurológicas e psiquiátricas. Objetivo: Neste trabalho objetivamos compreender e elucidar o papel da acetilação de histonas em processos envolvidos na modulação da memória utilizando o fármaco TSA e se baseia na hipótese de que a atividade de HDACs é essencial para a modulação das respostas de aprendizado na tarefa de esquiva inibitória (IA). Métodos: Ratos Wistar foram canulados bilateralmente na amígdala. Os efeitos das micro-infusões intra-amigdalares de TSA foram observados na consolidação e na extinção da memória após o treino na tarefa de esquiva inibitória e nos níveis do fator neurotrófico derivado do cérebro (BDNF) na BLA e no hipocampo referentes à consolidação da memória. Resultados: Os resultados demonstraram que a infusão intra-amigdalar de TSA 1.5 h, 3 h e 6 h após o treino na tarefa de esquiva inibitória resulta na melhora da memória de longa duração (LTM). TSA acelerou a extinção da memória quando infundido imediatamente pós-teste. Além disso, aumentou os níveis de BDNF no hipocampo. Conclusão: Estes resultados indicam que eventos epigenéticos possuem um papel importante no aprendizado e na memória através da atividade de HDACs.
Introduction: Memory formation involves changes in the expression of neuronal genes. Epigenetic remodeling of chromatin and reversible post-translational modifications in the DNA or in the histone proteins represent central mechanisms in the regulation of gene expression during brain development and early learning or memory retrieval. Imbalances in the levels of histone acetylation are associated with a wide variety of brain disorders. Histone deacetylases (HDACs) play a key role in homeostasis of histone acetylation and regulation of fundamental cellular activities, such as transcription, making them a focus of study. Evidences shows that the administration of histone deacetylases inhibitors (HDACis) restore the memory associated with the regulation of gene expression and improves memory in rats. Studies in animal models have shown that memory formation involves a series of biochemical changes in several areas of the central nervous system, which the hippocampus and basolateral amygdala (BLA) are the most highlighted. In this context, experimental drugs, such as trichostatin A (TSA), that act on epigenetic mechanisms, have recently been proposed as potential therapies for the treatment of memory and cognitive dysfunction associated with psychiatric and neurological disorders. Objective: In this work we aimed to understand and elucidate the role of histone acetylation in processes involved in memory modulation using the drug TSA and is based on the hypothesis that HDACs activity is essential for the modulation of learning answers in the inhibitory avoidance (IA) task. Methods: Wistar rats were cannulated bilaterally in the amygdala. The effects of TSA micro-infusions into the BLA were observed in the consolidation and extinction of memory after training in the inhibitory avoidance task and the levels of brain-derived neurotrophic factor (BDNF) in the BLA and hippocampus related to memory consolidation. Results: The results demonstrated that the TSA infusion into BLA 1.5 h , 3 h and 6 h posttraining in the inhibitory avoidance task results in improved long-term memory (LTM). TSA accelerated the extinction of memory when infused immediately post-test. In addition, increased levels of BDNF in the hippocampus. Conclusion: These results indicate that epigenetic events play an important role in learning and memory by HDAC activity.

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Rocha, Kellen Mariane Athaide. "Efeito neuroprotetor do ácido hidroxâmico de suberoilanilida (Saha), um inibidor de HDAC, em modelo de doença de Alzheimer induzida por injeção do peptídeo β-amilóide 1-42." Universidade Federal do Pampa, 2017. http://dspace.unipampa.edu.br:8080/jspui/handle/riu/3369.

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A doença de Alzheimer (DA) é uma desordem neurodegenerativa crônica caracterizada clinicamente pela perda progressiva de função cognitiva, distúrbios neuropsiquiátricos e comportamentais. Patologicamente esta doença caracteriza-se pelo acúmulo anormal do peptídeo β-amilóide (Aβ) no córtex e no hipocampo, emaranhados neurofibrilares intracelulares formados por tau hiperfosforilada, disfunção progressiva sináptica e, posteriormente perda neuronal. As opções terapêuticas disponíveis melhoram os sintomas, mas não impedem a progressão da doença, portanto, ainda está faltando uma estratégia terapêutica efetiva para DA. Há estudos relacionados à utilização de terapia epigenética para o tratamento da DA, a terapêutica mais desenvolvida é a que envolve a classe dos inibidores das deacetilases (HDACs). Assim, este trabalho tem por objetivo investigar o efeito protetor do inibidor da HDAC ácido hidroxâmico de suberoilanilida (SAHA) em um modelo de DA em camundongos. Para isso, foram utilizados 50 camundongos Swiss adultos, pesando entre 30-35 g, divididos em dois experimentos. No primeiro, os camundongos foram divididos em 6 grupos que receberam uma injeção de Aβ1-42 via intracerebroventricular (i.c.v.) no início da experiência (exceto o grupo Sham que foi utilizado como controle) para investigar a atividade das histonas acetiltransferase (HATs) e HDAC, determinação dos níveis do fator neurotrófico derivado do cérebro (BDNF), expressão do mRNA de BDNF e modulação da via (cAMP/PKA/CREB) em uma curva de tempo (6 horas, 1, 3, 7 e 21 dias). Ao final de cada tempo, os animais foram submetidos ao teste cognitivo e foram eutanasiados. O córtex pré-frontal e o hipocampo foram removidos para posteriores análises. No segundo experimento, os camundongos foram dividos em 4 grupos: Grupo Controle (sham+veículo); Grupo Aβ1-42 (Aβ1-42 + veículo); Grupo SAHA (25 mg/kg, via intraperitoneal) (sham + SAHA); Grupo Interação (Aβ1-42 + SAHA). O peptídeo Aβ1-42 ou o veículo foram infundidos por injeção i.c.v. e, um dia depois, iniciou-se o tratamento, por via i.p., durante 21 dias. Ao final do experimento os animais foram submetidos ao teste cognitivo, eutanásiados para retirada das estruturas cerebrais. As amostras foram utilizadas para a determinação dos níveis de BDNF, expressão do mRNA de BDNF, atividade enzimática das histonas (HDAC e HATs) e regulação da via cAMP/PKA/CREB. O presente estudo observou deficiências significativas causadas pela Aβ1-42 na memória (Labirinto Aquático de Morris), bem como causou desequilíbrio das enzimas HAT/HDAC, redução de cAMP, PKA e CREB e BDNF no córtex pré-frontal e hipocampo de camundongos. A inibição de HDAC, com SAHA demostrou neuroproteção nas alterações comportamentais e neuroquímicas induzidas por Aβ1-42. Estes dados mostram que a acetilação através da inibição do HDAC, desempenha um papel fundamental na mediação da memória e demonstra que SAHA poderá ser uma ferramenta médica promissora na abordagem terapêutica para o tratamento da DA.
Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized clinically by the progressive loss of cognitive function, neuropsychiatric and behavioral disorders. Pathologically this disease is characterized by the abnormal accumulation of β-amyloid peptide (Aβ) in the cortex and hippocampus, intracellular neurofibrillary tangles formed by hyperphosphorylated tau, progressive synaptic dysfunction and, later, neuronal loss. The available therapeutic options improve the symptoms, but they do not prevent the progression of the disease, therefore, an effective therapeutic strategy for AD is still lacking. There are studies related to the use of epigenetic therapy for the treatment of AD, the most developed therapy is that involving the class of deacetylase inhibitors (HDACs). Thus, this work aims to investigate the protective effect of the HDAC inhibitor hydroxamic acid suberoilanilide (SAHA) in an AD model in mice. For this, 50 Swiss adult mice weighing between 30-35 g were used, divided in two experiments. In the first, the mice were divided into 6 groups that received an injection of Aβ1-42 via the intracerebroventricular (i.c.v.) at the beginning of the experiment (except the Sham group that was used as control) to investigate histone activity acetyltransferase (HATs) and HDAC, determination of brain derived neurotrophic factor (BDNF) levels, expression of BDNF mRNA and modulation of the pathway (cAMP / PKA / CREB) in a time curve (6 hours, 1, 3, 7 and 21 days). At the end of each time, the animals were submitted to the cognitive test and were euthanized. The prefrontal cortex and hippocampus were removed for further analysis. In the second experiment, the mice were divided into 4 groups: Control Group (sham + vehicle); Group Aβ1-42 (Aβ1-42 + vehicle); SAHA group (25 mg / kg, intraperitoneal route) (sham + SAHA); Interaction Group (Aβ1-42 + SAHA). The Aβ1-42 peptide or vehicle was infused by i.c.v. and one day later the treatment was started i.p. for 21 days. At the end of the experiment the animals were submitted to the cognitive test, euthanasia for removal of the cerebral structures. The samples were used for the determination of BDNF levels, expression of BDNF mRNA, histone enzymatic activity (HDAC and HATs) and regulation of the cAMP / PKA / CREB pathway. The present study observed significant deficiencies caused by Aβ1-42 in memory (Morris Aquatic Labyrinth), as well as caused imbalance of HAT / HDAC enzymes, cAMP, PKA and CREB and BDNF reduction in the prefrontal cortex and hippocampus of mice. Inhibition of HDAC with SAHA demonstrated neuroprotection in behavioral and neurochemical changes induced by Aβ1-42. These data show that acetylation through inhibition of HDAC plays a key role in memory mediation and demonstrates that SAHA may be a promising medical tool in the therapeutic approach to AD.

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30

Perchermeier, Sophie [Verfasser], da Costa Clarissa [Akademischer Betreuer] Prazeres, Silvia [Gutachter] Lobmaier, da Costa Clarissa [Gutachter] Prazeres, and Percy A. [Gutachter] Knolle. "Chronic Schistosoma mansoni Infection during Pregnancy: Effects on Offspring’s T Cell Differentiation Capacity, Epigenetics and Memory T Cell Compartment / Sophie Perchermeier ; Gutachter: Silvia Lobmaier, Clarissa Prazeres da Costa, Percy A. Knolle ; Betreuer: Clarissa Prazeres da Costa." München : Universitätsbibliothek der TU München, 2021. http://d-nb.info/1230061045/34.

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Gour-ShenqKao and 高國勝. "The memory-associated alterations in protein and epigenetic signature." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/54518899760100306195.

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博士
國立成功大學
基礎醫學研究所
100
The formation of long term memories requires de novo protein synthesis shortly after the relevant experience. Two-dimensional gel electrophoresis was used to identify accumbal candidate proteins involved in the retrieval of a cue-mediated memory. Among the identified candidate proteins, a downregulated 14-3-3ζ protein was chosen and confirmed by Western immunoblotting. A polymer-mediated plasmid DNA delivery system was then used to overexpress 14-3-3ζ protein in the mouse nucleus accumbens before the CPP retrieval tests. Overexpression of accumbal 14-3-3ζ protein was found to diminish conditioned cue/context-mediated cocaine-induced CPP. Overexpression of accumbal 14-3-3ζ protein did not produce motor activity-impairing effect or alter local dopamine metabolism. Moreover, overexpression of accumbal 14-3-3ζ protein did not affect food-induced CPP. These results indicated that overexpressed accumbal 14-3-3ζ protein specifically decreased conditioned cue/context-mediated cocaine memory. In addition, epigenetic processes influence stress effects of early-life experience on learning and memory. In this study, a fear-potentiated startle was used to model the acquisition of traumatic event-related memory in female rats experiencing early life stress. We found that a 1 hr/day maternal and sibling separation throughout day 2-9 postpartum (D2-9PP) caused a decrease in the fear-potentiated startle, but not acoustic startle baseline, in female adult rats. The separation procedure did not affect baseline and acute stress-stimulated corticosterone (CORT) secretion but produced an increase in serum estradiol concentration. Moreover, the separation procedure did not affect histone 3 lysine 9 (H3K9) acetylation but decreased H3K9 mono- and tri-methylation in frontal cortices. Treatment with 5-aza-2’-deoxycytidine (AZA), an H3K9 acetylation enhancer, at 2 variant dosing regimens did not affect the separation-decreased fear-potentiated startle. Treatment with valproic acid (VPA), a histone deacetylase inhibitor, at 3 dosing regimens prior to daily separation reversed such a decrease in fear-potentiated startle. An effective VPA dosing regimen did not affect early life separation-produced increase in serum E2 secretion but reversed separation-decreased H3K9 mono- and tri-methylation in frontal cortices. Eight consecutive days of VPA and AZA treatments starting at D28PP were ineffective in altering the separation-decreased fear-potentiated startle, -increased E2 concentration, or -decreased frontal cortical mono-, tri-methylation. We suggest that decreased H3K9 mono- and tri-methylation in frontal cortex may be involved in early life separation-decreased fear memory formation. Early, but not late, VPA treatment is effective in treating early life stress-produced decrease in cued fear conditioning.

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32

Balta, Ana-Maria. "Epigenetic effects of learning and memory in the I-Ppo-I mouse." Thesis, 2016. https://hdl.handle.net/2144/19201.

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The epigenetics of the aging brain is a growing field of study that holds great promise for the discovery of mechanisms and potential treatments for neurodegenerative diseases. In this current study, a novel, accelerated aging murine model, the I-PpoI/Cre, or ICE (Inducible Changes in the Epigenome) mouse, is studied to test its potential for demonstrating the theory of the rearrangement of chromatin (RCM) as the main cause of aging, and in particular, the mechanism through which the brain ages. Immunohistochemistry and behavioral assays are utilized to determine whether there are morphological changes, inflammatory response, and changes in learning and memory. Results showed a significant increase in microglia and astrocytes, markers of inflammation, in I-PpoI/Cre mice compared to their Cre controls. Long term memory performance was also significantly decreased in the I-PpoI/Cre mice, demonstrated through contextual fear conditioning (CFC) testing, and Morris Water Maze (MWM) testing. Results from this study are in support of the I-PpoI/Cre mouse as a model of accelerated aging of the brain, with deficits in learning and memory. Further studies are needed to further characterize this murine model of accelerated aging.

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SIMANULLANG, BASTA, and 司峇塔. "The investigation of the epigenetic modification regulated mi-RNA induction in the hippocampus after spatial learning and memory formation." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/6n7xxg.

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碩士
國立中央大學
生命科學系
107
Behavior is driven by environmental stimulation that triggers brain activity with lots of molecular mechanisms. The process of learning and memory contains stimulation-induced changes that happen in the synaptic connections between neurons in the hippocampus, which plays a pivotal role in the formation of long term somatic and episodic memories. By Morris water maze experiment and RNA analysis, we show that some micro-RNAs (miRNA) are expressed differently between learned and unlearned mice. One of the miRNAs, miR-466f-3p, which belongs to post transcriptional regulator, is abundantly express in brain and generated in the intron-10 of Sfmbt2 gene. However, the mRNA expression of Sfmbt2 is significantly different from miR-466f-3p. Inhibition of epigenetic modification, such as DNA methylation, can affect gene expression. Treatment of 5’Aza-dC, a methyltransferase inhibitor, to the hippocampal primary culture neuron causes Bdnf, Nrf2, Sfmbt2 mRNA and miR466f-3p expression increased. However, the methylation pattern in the promoter region of the miR-466f cluster is not significantly different between learned and unlearned mice. The evidence show that the changes of DNA methylation under the stress of the Morris water maze indirectly participate in the regulating of miR-466f-3p induction in the hippocampus-dependent spatial learning and memory formation. Keywords: Epigenetic, mi-RNAs induction, Methylation

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Pinc, Jan. "Vznik, přenos a ekologický význam apomixie v rodě Hieracium s.str.: role genetických a epigenetických mechanismů." Doctoral thesis, 2020. http://www.nusl.cz/ntk/nusl-436152.

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Apomixis (asexual reproduction by seeds) has the considerable potential in agriculture and crop breeding due to its ability to produce genetically identical progenies in a form of persistent propagules, i.e. seeds. However, the processes laying behind the origin of apomixis and connected molecular mechanisms are still unknown. Despite the fact, that apomicts are considered to be an evolutionary dead-ends, they are often more widely distributed than their sexual relatives (this phenomenon is commonly referred to as geographical parthenogenesis (GP). Although this phenomenon is studied for decades, its causes are still not fully understood. Importantly, several recent studies pointed out that apomicts with limited genetic variability can at some extent react to changing environment through changes in gene transcription by epigenetic modifications. It is generally assumed, that hybridisation and polyploidization played a crucial role in the emergence of apomixis. For this reason, presented studies test the putative origin of selected polyploid apomicts and if the interspecific hybridisation between diploid sexuals triggers polyploidization using predominantly polyploid and apomictic genus Hieracium s. str. Surprisingly, the presented study demonstrates the hybrid origin of almost all investigated...

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Al-Rikabi, Aaiad H. A., Desmond J. Tobin, Kirsten Riches-Suman, and M. Julie Thornton. "Dermal fibroblasts cultured from donors with type 2 diabetes mellitus retain an epigenetic memory associated with poor wound healing responses." 2020. http://hdl.handle.net/10454/18438.

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Yes
The prevalence of Type 2 diabetes mellitus (T2DM) is escalating globally. Patients suffer from multiple complications including the development of chronic wounds that can lead to amputation. These wounds are characterised by an inflammatory environment including elevated tumour necrosis factor alpha (TNF-α). Dermal fibroblasts (DF) are critical for effective wound healing, so we sought to establish whether there were any differences in DF cultured from T2DM donors or those without diabetes (ND-DF). ND- and T2DM-DF when cultured similarly in vitro secreted comparable concentrations of TNF-α. Functionally, pre-treatment with TNF-α reduced the proliferation of ND-DF and transiently altered ND-DF morphology; however, T2DM-DF were resistant to these TNF-α induced changes. In contrast, TNF-α inhibited ND- and T2DM-DF migration and matrix metalloprotease expression to the same degree, although T2DM-DF expressed significantly higher levels of tissue inhibitor of metalloproteases (TIMP)-2. Finally, TNF-α significantly increased the secretion of pro-inflammatory cytokines (including CCL2, CXCL1 and SERPINE1) in ND-DF, whilst this effect in T2DM-DF was blunted, presumably due to the tendency to higher baseline pro-inflammatory cytokine expression observed in this cell type. Collectively, these data demonstrate that T2DM-DF exhibit a selective loss of responsiveness to TNF-α, particularly regarding proliferative and secretory functions. This highlights important phenotypic changes in T2DM-DF that may explain the susceptibility to chronic wounds in these patients.
This study was funded by an Iraqi government studentship to AHAA-R.

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"The Dirty Joke of Cyberpunk or the Humanism of Posthumanism in the Cyberpunk Tradition: Epigenetic Memory and Technology in Gibson's Neuromancer and Stephenson's Snow Crash." Master's thesis, 2013. http://hdl.handle.net/2286/R.I.17778.

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abstract: What does it mean to be human or for that matter, posthuman, according to a cyberpunk? This paper navigates the experience of being human in the dystopian and highly technologized future worlds found within the cyberpunk literary tradition of the 1980s and early 1990s. This work explores the implication of what it means to be posthuman in these worlds, which are comprised of virtual realities and disembodied identities. This project first addresses posthumanism as a critical theory and its destabilization of the traditional concept of humanism with particular attention to the relationship between the human being and technology. After building a theoretical framework of posthumanism based on works by Martin Heidegger, Jacques Derrida, and Bernard Stiegler, this paper then offers a survey of the cyberpunk tradition and the key themes developed and examined within the genre. The project then investigates two seminal works of the cyberpunk movement, William Gibson's 1984 novel, Neuromancer, and Neal Stephenson's 1992 work, Snow Crash, in order to trace a becoming posthuman as it is found within cyberpunk. As this paper further explains, the process of uncovering the posthuman within these texts produces a sense of loss and also nostalgia for a previous experience of being human which was already posthuman. The cyberpunk tradition and these novels in particular, reveal that there has always already been a degree of indeterminacy surrounding the question of what it means to be human. Through destabilizing traditionally held conceptions of humanism, cyberpunk and posthumanism offer the potential to rethink ourselves and our comportment towards the world knowing that technology always already informs our experience of being human.
Dissertation/Thesis
M.A. English 2013

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Löns, Sebastian. "Epigenetik in der Schizophrenie und der Einfluss von Histon-Deacetylasen auf die Arbeitsgedächtnisfunktion." Doctoral thesis, 2015. http://hdl.handle.net/11858/00-1735-0000-0023-963D-C.

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Ganguly, Diep. "Training Memory: Exploring the Intersection of Plant Stress Signalling and DNA Methylation." Phd thesis, 2018. http://hdl.handle.net/1885/145958.

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Plants are sessile organisms living in a dynamic environment to which they must continually acclimatize in order to maximise their reproductive potential. This plasticity is achieved through many complex and intricate signalling pathways that allow for the continuous perception, response, and adjustments to new environmental stimuli. A growing body of evidence suggests that such pathways are not merely static but dynamic and can be primed following repeated activation, thus affecting enhanced responses to recurring stresses. Such examples of priming have led to a notion that plants have some capacity to form stress memories of past environmental perturbations. However, the full extent and nature of such memory, and the machinery involved to store and transmit these, remain enigmatic. One prospective mechanism is the involvement of heritable, yet rapid and reversible, chromatin marks that, theoretically, could be shaped by the environment to convey a regulatory effect on the expression of the underlying genotype, thus acting as an epigenetic layer of regulation. This thesis explores the potential intersection of stress signalling pathways and chromatin variation, specifically DNA methylation, to co-ordinate plant stress responses. First, mechanistic insights into the operation of a SAL1-PAP-XRN retrograde signalling pathway to fine-tune plant physiology under drought are presented. A key finding was that this pathway complements canonical ABA signalling to induce stomatal closure, thus minimising water-loss under water limited conditions. Furthermore, the SAL1-PAP-XRN pathway was found to effect chromatin patterns, specifically DNA methylation at short transposable elements. These observations implicate cross-talk with the RNA directed DNA methylation pathway, however, the exact mechanism for this interaction remains to be identified. Multiple investigations were performed to test for stress-induced changes in DNA methylation that could potentially regulate responses to recurring stress, thus conveying a memory. A transgenerational recurring drought stress experiment tested whether descendants of drought-exposed lineages displayed greater drought tolerance (transgenerational memory). For the majority of traits tested, including plant growth rate and drought survival, offspring from plant lineages exposed to successive generations of repeated drought stress performed comparably to those from control lineages. However, memory was demonstrated in the form of enhanced seed dormancy, in drought stressed lineages, that persisted at least one generation removed from stress. Whether this capacity for memory could be related to the type or severity of stress applied, or species examined, remains to be investigated further. The transgenerational drought experiment was paired with a recurring excess-light stress experiment to investigate memory within a generation. Not only did this treatment lead to priming of plant photosynthetic behaviour, indicative of a greater capacity to withstand abrupt increases in light intensity, but new leaves from stressed plants, developed in the absence of stress, also showed altered photosynthetic characteristics compared to unstressed counterparts. Such observations are consistent with the mitotic transmission of stress-induced traits. Given multiple demonstrations of memory, comparisons were made to unstressed controls to test for any correlating changes in DNA methylation that might explain the phenomena observed. However, in both experiments, observations of memory were found to be independent of large-scale conserved changes in DNA methylation discounting it as a conveyor of plant stress memories, under these conditions, raising questions regarding the mechanism(s) responsible for the examples of memory observed herein. Ultimately, this thesis systematically evaluates the notion that plants are able to form genuine memories, potentially underpinned by reversible chromatin marks, that may facilitate acclimation to local environments on a relatively rapid scale compared to the fixation of adaptive genetic polymorphisms. Any capacity for plant stress memories may provide avenues for further epigenomic based agronomic tools to improve crop stress tolerance. However, the nature of such memories observed here appear subtle and nuanced, and are forgotten beyond a generation. Further characterisation and mechanistic understanding of mitotic memory mechanisms, however, may still hold potential. It was also observed that stress signalling pathways can interact with those involved in chromatin modification, giving novel insight into their mechanistic functioning and the how the onset of stress may induce chromatin changes. Despite this potential, the DNA methylome was found to be relatively impervious to stress-induced changes and, thus, is an unlikely memory mechanism.

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Stilling, Roman. "The role of Kat2a during memory formation and chromatin plasticity in the aging murine hippocampus." Doctoral thesis, 2013. http://hdl.handle.net/11858/00-1735-0000-0001-BAC5-2.

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Brazão, João António Lima de Andrade Conde. "Relatório de estágio e monografia intitulada :"mecanismos epigenéticos na formação de memória e capacidades cognitivas"." Master's thesis, 2017. http://hdl.handle.net/10316/83661.

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Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia
A habilidade do organismo humano em adaptar o seu comportamento em resposta a estímulos ambientais ao longo do tempo, fundamenta-se na plasticidade estrutural e funcional do SNC. É atualmente conhecido que os processos em torno da memória celular (diferenciação), e da memória neurológica têm similaridades, não só ao nível da sua génese como também da sua regulação, orquestrada por mecanismos epigenéticos. A definição molecular moderna de epigenética consiste no conjunto de alterações na estrutura base da cromatina que, coletivamente, originam e propagam diferentes padrões de expressão de genes, transcrição, e silenciamento em relação ao mesmo genoma que não são explicados por mudanças na sequência de DNA. Marcas epigenéticas como a metilação do DNA e modificações pós-tradução das histonas têm vindo a comprovar-se cada vez mais como imprescindíveis reguladores dos processos de memória. As suas funções de regulação dinâmica da transcrição de genes em resposta à ativação neuronal mostram-se relevantes e influentes no processo de formação de memória. A natureza persistente, mesmo após divisão celular, de mecanismos como a metilação do DNA sugere também a existência de um papel da epigenética na manutenção da memória previamente formada. O conteúdo da presente monografia tem como foco a ligação entre determinados processos envolvidos na formação e manutenção de memória e capacidades cognitivas, compreendendo vias de sinalização comuns a ambos os tipos de memória referidos, e os mecanismos epigenéticos implicados na regulação desses mesmos processos e consequentes respostas, dependentes de uma articulação e encadeamento com um elevado nível de precisão temporal e especificidade.
The ability of the human organism to adapt its behavior in response to environmental stimuli through time is based on the structural and functional plasticity of the CNS. It is known that the processes regarding cellular memory (differentiation) and neurological memory have similarities, not only on the level of their genesis but of their regulation as well, orchestrated by epigenetic mechanisms. The modern molecular definition of Epigenetics comprehends the range of modifications in the basic chromatin structure that, collectively, originate and spread different gene expression patterns, transcription and silencing in relation to the same genome that are not explained by changes in the DNA sequence. Epigenetic tags like DNA methylation and histone post-translational modifications have been increasingly seen as crucial regulators of memory processes. Their functions of dynamic regulation of gene transcription in answer to the neuronal activation have been shown to be relevant and influential in memory formation. The persistent nature of mechanisms like DNA methylation, even after cell division, also suggests the existence of a role to epigenetics on the maintenance of previously formed memory. The content of the present monography spotlights the connection of particular processes involved in the formation and maintenance of memory and cognition, including signaling pathways common to both types of memory (cellular and neuronal) and the epigenetic mechanisms implicated on the regulation of these same processes and subsequent outcomes, dependent of an articulation and sequencing comprising a high level of temporal precision and specificity.

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Urban, Inga. "The Role of Lysine Acetyltransferase Tip60 in the Murine Hippocampus." Doctoral thesis, 2014. http://hdl.handle.net/11858/00-1735-0000-0022-6046-5.

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Shomroni, Orr. "Development of algorithms and next-generation sequencing data workflows for the analysis of gene regulatory networks." Doctoral thesis, 2017. http://hdl.handle.net/11858/00-1735-0000-0023-3E0C-8.

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Rajput, Ashish. "Using cell type-specific methods to understand molecular processes in the brain." Doctoral thesis, 2018. http://hdl.handle.net/11858/00-1735-0000-002E-E63D-B.

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Navarro, Sala Magdalena. "Changes in gene expression linked to Alzheimer's disease and "healthy" cognitive aging." Doctoral thesis, 2018. http://hdl.handle.net/11858/00-1735-0000-002E-E59C-E.

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Dissertations / Theses on the topic 'Epigenetic memory'

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