Epigenetic regulation of neonatal cardiomyocytes differentiation

Kou, Cecy Ying-Chuck; Lau, Samantha Lai-Yee; Au, Ka-Wing; Leung, P. Y.; Chim, Stephen S.C.; Fung, Kwok‐Pui; Waye, Mary Miu Yee; Tsui, Stephen Kwok‐Wing

doi:10.1016/j.bbrc.2010.08.064

Cited by 29 publications

(34 citation statements)

References 24 publications

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“…These findings illustrate an important role of DNA methylation in cardiomyocyte terminal differentiation and further implicate methylation as a vital factor in the induction of dexamethasone-mediated effects. Other studies also support the importance of methylation in perpetuating cardiomyocyte terminal differentiation (Kou et al, 2010;Gilsbach et al, 2014). For instance, Kou et al (2010) found that inhibition of DNA methylation in cardiomyocytes using 5-azacytidine resulted in increased DNA synthesis and delayed terminal differentiation during the development of postnatal days 7 and 10 rats.…”

Section: Discussionmentioning

confidence: 82%

“…Other studies also support the importance of methylation in perpetuating cardiomyocyte terminal differentiation (Kou et al, 2010;Gilsbach et al, 2014). For instance, Kou et al (2010) found that inhibition of DNA methylation in cardiomyocytes using 5-azacytidine resulted in increased DNA synthesis and delayed terminal differentiation during the development of postnatal days 7 and 10 rats. This is consistent with the present findings that dexamethasone treatment induced terminal differentiation prematurely and was associated with hypermethylation of the CcnD2 gene promoter.…”

Section: Discussionmentioning

confidence: 82%

“…Although much is still unknown about the mechanisms underlying the transition of cardiomyocytes from proliferative to terminally differentiated binucleation, many studies have been focused on molecules involved in cell cycle regulation and cytokinesis, as well as epigenetic modifications (Engel et al, 2006;Kou et al, 2010;Liu et al, 2010;Di Stefano et al, 2011). Cyclin D2 is a cell cycle promoter that plays an important role in the regulation of cardiomyocyte proliferation and terminal differentiation (McGill and Brooks, 1995;Brooks et al, 1997;Poolman and Brooks, 1998;Nagai et al, 2001;Paradis et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Dexamethasone Induces Cardiomyocyte Terminal Differentiation via Epigenetic Repression of Cyclin D2 Gene

Dasgupta

Kanna

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Dexamethasone treatment of newborn rats inhibited cardiomyocyte proliferation and stimulated premature terminal differentiation of cardiomyocytes in the developing heart. Yet mechanisms remain undetermined. The present study tested the hypothesis that the direct effect of glucocorticoid receptor-mediated epigenetic repression of cyclin D2 gene in the cardiomyocyte plays a key role in the dexamethasone-mediated effects in the developing heart. Cardiomyocytes were isolated from 2-day-old rats. Cells were stained with a cardiomyocyte marker a-actinin and a proliferation marker Ki67. Cyclin D2 expression was evaluated by Western blot and quantitative real-time polymerase chain reaction. Promoter methylation of CcnD2 was determined by methylated DNA immunoprecipitation (MeDIP). Overexpression of Cyclin D2 was conducted by transfection of FlexiCcnD2 (1CcnD2) construct. Treatment of cardiomyocytes isolated from newborn rats with dexamethasone for 48 hours significantly inhibited cardiomyocyte proliferation with increased binucleation and decreased cyclin D2 protein abundance. These effects were blocked with Ru486 (mifepristone). In addition, the dexamethasone treatment significantly increased cyclin D2 gene promoter methylation in newborn rat cardiomyocytes. 5-Aza-2'-deoxycytidine inhibited dexamethasone-mediated promoter methylation, recovered dexamethasone-induced cyclin D2 gene repression, and blocked the dexamethasone-elicited effects on cardiomyocyte proliferation and binucleation. In addition, the overexpression of cyclin D2 restored the dexamethasone-mediated inhibition of proliferation and increase in binucleation in newborn rat cardiomyocytes. The results demonstrate that dexamethasone acting on glucocorticoid receptors has a direct effect and inhibits proliferation and stimulates premature terminal differentiation of cardiomyocytes in the developing heart via epigenetic repression of cyclin D2 gene.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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Dexamethasone Induces Cardiomyocyte Terminal Differentiation via Epigenetic Repression of Cyclin D2 Gene

Dasgupta

Kanna

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…While the study design does not permit exclusion of a possible contribution of systemic effects of 5azato the observed cardiac phenotype, the in vivo findings are consistent with two recent in vitro studies in cultured neonatal rat cardiomyocytes , which suggested that 5azainduces cardiomyocyte proliferation and inhibits endothelin-induced cardiomyocyte binucleation (Felician et al, 2014b;Kou et al, 2010;Paradis et al, 2014). These striking effects of 5azaon cardiomyocyte binucleation are particularly interesting given that hypomethylating agents such as 5azaare commonly used as anti-cancer drugs and have anti-proliferative effects in other cell types.…”

Section: Discussionsupporting

confidence: 80%

DNA methylation and chromatin dynamics during postnatal cardiomyocyte maturation

Sim

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“…During mammalian development, the organism must faithfully and precisely orchestrate the expression of various gene programmes in a temporally and spatially accurate manner [3][4][5][6][7][8]. Similarly, the precise growth of the mammalian heart during embryonic development and terminal differentiation in the adult is dependent on the accurate activation of a gene programme that involves enzymes controlling nucleosome remodeling, histone modification, and DNA methylation [9][10][11][12][13][14]. Failure to properly orchestrate these mechanisms results in deleterious phenotypes like septal defects, atrioventricular malformations, or developmental absence of right or the left heart, if not lethality during embryogenesis at all [15,16].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic mechanisms in cardiac development and disease

Vallaster¹,

Vallaster²,

Wu³

2012

ABBS

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During mammalian development, cardiac specification and ultimately lineage commitment to a specific cardiac cell type is accomplished by the action of specific transcription factors (TFs) and their meticulous control on an epigenetic level. In this review, we detail how cardiacspecific TFs function in concert with nucleosome remodeling and histone-modifying enzymes to regulate a diverse network of genes required for processes such as cell growth and proliferation, or epithelial to mesenchymal transition (EMT), for instance. We provide examples of how several cardiac TFs, such as Nkx2.5, WHSC1, Tbx5, and Tbx1, which are associated with developmental and congenital heart defects, are required for the recruitment of histone modifiers, such as Jarid2, p300, and Ash2l, and components of ATP-dependent remodeling enzymes like Brg1, Baf60c, and Baf180. Binding of these TFs to their respective sites at cardiac genes coincides with a distinct pattern of histone marks, indicating that the precise regulation of cardiac gene networks is orchestrated by interactions between TFs and epigenetic modifiers. Furthermore, we speculate that an epigenetic signature, comprised of TF occupancy, histone modifications, and overall chromatin organization, is an underlying mechanism that governs cardiac morphogenesis and disease.

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Epigenetic regulation of neonatal cardiomyocytes differentiation

Cited by 29 publications

References 24 publications

Dexamethasone Induces Cardiomyocyte Terminal Differentiation via Epigenetic Repression of Cyclin D2 Gene

Dexamethasone Induces Cardiomyocyte Terminal Differentiation via Epigenetic Repression of Cyclin D2 Gene

DNA methylation and chromatin dynamics during postnatal cardiomyocyte maturation

Epigenetic mechanisms in cardiac development and disease

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