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Deregulation of the Transcriptional Repressor E2F6 in Myocardium Leads to Gene Activation and Dilated CardiomyopathyRueger, Jennifer 04 May 2011 (has links)
The E2F family of transcription factors regulate cellular growth, death and differentiation, but their role in cardiac biology remains to be fully explored. We hypothesized that the balance of the E2F pathway would determine cardiac development and function. We provide evidence for this via modulation of the E2F6 repressor, in a transgenic (Tg) mouse model. Targeted expression of E2F6 in the heart led to dilated cardiomyopathy (DCM) and death. Microarray analysis revealed that E2F responsive pathways were activated in Tg mice. Furthermore, we found that E2F6 and YY1 (E2F-co-factor) were translocated to the nucleus in Tg mice, providing a potential mechanism for the observed transcriptional activation. We also observed a marked decrease of Connexin43 protein in the myocardium, and reduced atrial conductivity in Tg mice which may lead to reduced cardiac function. The data demonstrates a novel role for E2F pathway outside of cell cycle control in the heart.
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Deregulation of the Transcriptional Repressor E2F6 in Myocardium Leads to Gene Activation and Dilated CardiomyopathyRueger, Jennifer 04 May 2011 (has links)
The E2F family of transcription factors regulate cellular growth, death and differentiation, but their role in cardiac biology remains to be fully explored. We hypothesized that the balance of the E2F pathway would determine cardiac development and function. We provide evidence for this via modulation of the E2F6 repressor, in a transgenic (Tg) mouse model. Targeted expression of E2F6 in the heart led to dilated cardiomyopathy (DCM) and death. Microarray analysis revealed that E2F responsive pathways were activated in Tg mice. Furthermore, we found that E2F6 and YY1 (E2F-co-factor) were translocated to the nucleus in Tg mice, providing a potential mechanism for the observed transcriptional activation. We also observed a marked decrease of Connexin43 protein in the myocardium, and reduced atrial conductivity in Tg mice which may lead to reduced cardiac function. The data demonstrates a novel role for E2F pathway outside of cell cycle control in the heart.
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Deregulation of the Transcriptional Repressor E2F6 in Myocardium Leads to Gene Activation and Dilated CardiomyopathyRueger, Jennifer January 2011 (has links)
The E2F family of transcription factors regulate cellular growth, death and differentiation, but their role in cardiac biology remains to be fully explored. We hypothesized that the balance of the E2F pathway would determine cardiac development and function. We provide evidence for this via modulation of the E2F6 repressor, in a transgenic (Tg) mouse model. Targeted expression of E2F6 in the heart led to dilated cardiomyopathy (DCM) and death. Microarray analysis revealed that E2F responsive pathways were activated in Tg mice. Furthermore, we found that E2F6 and YY1 (E2F-co-factor) were translocated to the nucleus in Tg mice, providing a potential mechanism for the observed transcriptional activation. We also observed a marked decrease of Connexin43 protein in the myocardium, and reduced atrial conductivity in Tg mice which may lead to reduced cardiac function. The data demonstrates a novel role for E2F pathway outside of cell cycle control in the heart.
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Identification de cibles et régulateurs de la méthylation de l'ADN chez la souris / Identification of targets and regulators of DNA methylation in miceAuclair, Ghislain 22 October 2015 (has links)
La méthylation de l’ADN est une modification épigénétique qui prend place durant le développement embryonnaire sur le génome des Mammifères. Durant ma thèse, j’ai déterminé les cinétiques de mise en place de la méthylation de l’ADN sur le génome murin au cours de l’embryogénèse précoce. J’ai identifié les rôles spécifiques et redondants des ADN méthyltransférases DNMT3a et DNMT3b dans ce processus. J’ai également étudié le rôle de deux facteurs dans la mise en place de la méthylation de l’ADN dans l’embryon. Premièrement, j’ai déterminé que l’enzyme G9a joue un rôle essentiel pour la répression et le recrutement de la méthylation de l’ADN à des sites spécifiques du génome, incluant en particulier des promoteurs à ilots CpG de gènes méiotiques. Deuxièmement, l’étude du facteur E2F6 m’a permis de montrer que cette protéine est elle aussi impliquée dans le recrutement de la méthylation de l’ADN, et ce à des promoteurs de gènes méiotiques distincts de ceux régulés par G9a. / DNA methylation is an epigenetic modification which is established during embryonic development on the mammalian genome. In my thesis, I determined the kinetics of DNA methylation acquisition on the mouse genome during early embryogenesis, and determined the specific and redundant roles of the DNA methyltransferases DNMT3a and DNMT3b in this process. I also studied the roles of two factors involved in setting up DNA methylation in embryos. First, I determined that the G9a enzyme plays an essential role for the in vivo repression and DNA methylation of specific genomic sites, including in particular the CpG island promoters of germline genes. Second, the study of the E2F6 factor allowed me to show that this protein is also involved in recruiting DNA methylation at a set of germline gene promoters than are distinct from those regulated by G9a.
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