Rb and p130 control cell cycle gene silencing to maintain the postmitotic phenotype in cardiac myocytes

Sdek, Patima; Zhao, Peng; Wang, Yaping; Huang, C.; Ko, Christopher Y.; Butler, Peter C.; Weiss, James N.; MacLellan, W. Robb

doi:10.1083/jcb.201012049

Cited by 157 publications

(192 citation statements)

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“…pluripotency > mesoderm > cardiac progenitors > cardiomyocytes) [56,57]. There is a progressive compaction of nucleic material during differentiation of ESCs [58] and also during cardiomyocyte maturation [59]. Chromatin compaction and gene silencing are particularly prevalent at pluripotency loci and are coupled with a global shutdown of pluripotency in somatic cells [58].…”

Section: Dynamic Changes In the Epigenome During Cardiomyocyte Differmentioning

confidence: 99%

Resetting the epigenome for heart regeneration.

Quaife-Ryan

Sim

Porrello

et al. 2016

Seminars in Cell & Developmental Biology

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In contrast to adults, recent evidence suggests that neonatal mice are able to regenerate following cardiac injury. This regenerative capacity is reliant on robust induction of cardiomyocyte proliferation, which is required for faithful regeneration of the heart following injury. However, cardiac regenerative potential is lost as cardiomyocytes mature and permanently withdraw from the cell cycle shortly after birth. Recently, a handful of factors responsible for the regenerative disparity between the adult and neonatal heart have been identified, but the proliferative response of adult cardiomyoctes following modulation of these factors rarely reaches neonatal levels. The inefficient re-induction of proliferation in adult cardiomyocytes may be due to the epigenetic landscape, which drastically changes during cardiac development and maturation. In this review, we provide an overview of the role of epigenetic modifiers in developmental processes related to cardiac regeneration. We propose an epigentic framework for heart regeneration whereby adult cardiomyocyte identity requires resetting to a neonatal-like state to facilitate cell cycle re-entry and regeneration following cardiac injury.

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Section: Dynamic Changes In the Epigenome During Cardiomyocyte Differmentioning

confidence: 99%

Resetting the epigenome for heart regeneration.

Quaife-Ryan

Sim

Porrello

et al. 2016

Seminars in Cell & Developmental Biology

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“…Our results indicate that Meis1 expression and nuclear localization in cardiomyocytes coincide with cell cycle arrest. Cardiomyocyte cell cycle exit is associated with downregulation of positive cell cycle regulators (CDK2, CDK3, CDK4, CCND1, and CDK cofactors) and induction of cell cycle inhibitors (CDKI, members of the INK4 and CIP/KIP families) [10,[17][18][19][20]. We identified conserved Meis1 domains in only two key CDK inhibitors, namely, p16 and p21, which are known to regulate all three cell cycle checkpoints.…”

Section: Introductionmentioning

confidence: 99%

Meis1 Regulates Postnatal Cardiomyocyte Cell Cycle Arrest

Muralidhar

Sadek

2016

Etiology and Morphogenesis of Congenital Heart Disease

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The neonatal mammalian heart is capable of substantial regeneration following injury through cardiomyocyte proliferation (Porrello et al, Science 331:1078-1080 Proc Natl Acad Sci U S A 110:187-92, 2013). However, this regenerative capacity is lost by postnatal day 7 and the mechanisms of cardiomyocyte cell cycle arrest remain unclear. The homeodomain transcription factor Meis1 is required for normal cardiac development but its role in cardiomyocytes is unknown (Paige et al, Cell 151:221-232, 2012; Wamstad et al, Cell 151: 206-220, 2012). Here we identify Meis1 as a critical regulator of the cardiomyocyte cell cycle. Meis1 deletion in mouse cardiomyocytes was sufficient for extension of the postnatal proliferative window of cardiomyocytes and for reactivation of cardiomyocyte mitosis in the adult heart with no deleterious effect on cardiac function. In contrast, overexpression of Meis1 in cardiomyocytes decreased neonatal myocyte proliferation and inhibited neonatal heart regeneration. Finally, we show that Meis1 is required for transcriptional activation of the synergistic CDK inhibitors p15, p16, and p21. These results identify Meis1 as a critical transcriptional regulator of cardiomyocyte proliferation and a potential therapeutic target for heart regeneration.

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“…The first report of successfully reversing the post-mitotic state of adult CMs demonstrated the importance of epigenetic regulation of cell cycle gene silencing in adult CMs [5]. Similar to senescent cells, the gene-silencing epigenetic histone mark H3K9me3 becomes enriched on promoters of cell cycle progression genes (cdc2 and Plk1) during the differentiation from fetal to adult CMs.…”

mentioning

confidence: 99%

“…Recent reports suggest that there are at least three different levels of regulations limiting CM proliferation: 1) pre-transcriptional heterochromatin-mediated gene silencing of positive cell cycle regulators [5], 2) post-transcriptional regulation through microRNAs (miRNAs) [6], and now 3) transcriptional activation of negative cell cycle regulators [7] ( Figure 1).…”

mentioning

confidence: 99%