When silence is broken: polycomb group proteins in heart development.

Heart morphogenesis is a complex process that involves orchestration of cardiac cell commitment, differentiation, proliferation, and migration. Much progress has been made toward understanding the molecular mechanisms that regulate these events during normal development. However, the role of chromatin modification for heart development has received comparatively little attention, despite the fact that epigenetic modifications establish a cell-type–specific chromatin pattern that is of paramount importance for cell commitment and differentiation. The polycomb group proteins are key regulators of gene expression during development and differentiation, silencing genes via regulation of the chromatin structure (Figure). Polycomb group proteins act in complexes that have specific catalytic functions important for transcriptional repression. In mammals, 2 major Polycomb group complexes exist: Polycomb repressive complex 1 (PRC1) and 2 (PRC2). Whereas PRC1 ubiquitylates histone H2A on Lys119,1 PRC2 catalyzes the dimethylation and trimethylation of H3 on Lys27, generating H3K27me2/3.2 Generally, the H3K27me2/3 mark is specifically recognized by the chromodomain of Polycomb (Pc), a subunit of PRC1 complexes,1 which provides a platform for PRC1 recruitment and Polycomb-mediated transcriptional repression. EZH1/2, SUZ12, and EED are core components of the PRC2 complex. The catalytic function of PRC2 requires either EZH1 or EZH2, both of which possess histone lysine methyltransferase activities. EZH1and EZH2containing complexes share an overlapping set of target genes, which suggests that they might have partially redundant functions.3,4 However, recent evidence suggests that EZH1 might catalyze trimethylation of H3 on Lys4, generating the active epigenetic mark H3K4me3, which calls into question the concept of redundancy between Ezh1 and Ezh2.5 In vitro, EZH2 has a higher catalytic activity than EZH1 with respect to H4K27 trimethylation, but PRC2-EZH1 more effectively induces chromatin compaction and represses transcription.3 Moreover, the 2 homologues have distinct spatial and temporal expression patterns, with EZH1 being more ubiquitously expressed and more abundant in adult organs,3 which suggests that the 2 complexes may have both common and distinct functions.3,4 In the current issue of Circulation Research, He and colleagues6 analyze the role of PRC2 in heart development. Previous studies have demonstrated the essential role of PRC2 during early embryonic development, because mice deficient for the core components of the complex display early embryonic lethality at embryonic day 7.5 through 8.5.7–9 To study the role of PRC2 in heart development, He et al6 conditionally inactivated Ezh2 using 2 different Cre lines: Nkx2-5:Cre, which is active in cardiac progenitors and cardiomyocytes, and TnT:Cre, active only in cardiomyocytes. Interestingly, inactivation of Ezh2 by Nkx2-5:Cre (Ezh2) led to embryonic lethality and congenital heart defects, including compact myocardial hypoplasia, hypertrabeculation, and ventricular and atrial septal defects, whereas inactivation of Ezh2 with TnT:Cre (Ezh2) did not show an overt phenotype despite a modest upregulation of some target genes (Figure). The absence of an overt phenotype in Ezh2 mice was attributed to redundant functions of Ezh1 and Ezh2, because inactivation of the nonredundant PRC2 component Eed by TnT:Cre led to embryonic lethality and heart defects, including compact myocardial hypoplasia. However, Eed embryos did not show septal defects, which implies that the PRC2-EZH2 complex has distinct functions in regulating the chromatin state of cardiac progenitor cells. Using genome-wide RNA expression profiling of wild-type and Ezh2-deficient hearts combined with chromatin immunoprecipitation, He et al6 identified genes directly repressed by EZH2, including cell cycle regulators, transcriptional regulators of different developmental programs, and molecules important for cardiomyocyte function.6 PRC2 regulates a number of these genes in other cell types, which suggests a common mode of action by which PRC2 regulates cellular decisions.10,11 Potentially most important for the decreased cardiomyocyte proliferation in Ezh2 hearts is the observed upregulation of the cell cycle inhibitors Ink4a (p16) and Ink4b (p15). Comparative expression analysis of Ezh2 hearts, which did not show an overt phenotype, with malformed Eed and Ezh2 hearts revealed that derepression of Ink4a/b, Isl1, and Pax6 is closely correlated with the phenotype. In contrast, upregulation of Six1 (which is highly expressed in cardiac progenitor cells but not in cardiomyocytes) was observed in both Ezh2 and Ezh2 hearts, which indicates that it is not sufficient to cause congenital heart defects. Furthermore, PRC-EZH2 was also required for correct spatiotemporal regulation of typical cardiac genes such as Hcn4, Mlc2a, and Bmp10. Intriguingly, the derepression of key regulatory genes of different cell lineages (such as Pax6) observed in the mutant mice was not sufficient to divert The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Max Planck Institute for Heart and Lung Research, Department of Cardiac Development and Remodelling, Bad Nauheim, Germany. Correspondence to Thomas Braun, Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Ludwigstraße 43, Bad Nauheim, Germany. E-mail [email protected] (Circ Res. 2012;110:372-374.) © 2012 American Heart Association, Inc.