When Silence is Broken

Abstract

See related article, pages 406–415 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. EZH1- and EZH2-containing 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 …