Abstract
In proliferating cells, where most Polycomb repressive complex 2 (PRC2) studies have been performed, gene repression is associated with PRC2 trimethylation of H3K27 (H3K27me3). However, it is uncertain whether PRC2 writing of H3K27me3 is mechanistically required for gene silencing. Here, we studied PRC2 function in postnatal mouse cardiomyocytes, where the paucity of cell division obviates bulk H3K27me3 rewriting after each cell cycle. EED (embryonic ectoderm development) inactivation in the postnatal heart (EedCKO) caused lethal dilated cardiomyopathy. Surprisingly, gene upregulation in EedCKO was not coupled with loss of H3K27me3. Rather, the activating histone mark H3K27ac increased. EED interacted with histone deacetylases (HDACs) and enhanced their catalytic activity. HDAC overexpression normalized EedCKO heart function and expression of derepressed genes. Our results uncovered a non-canonical, H3K27me3-independent EED repressive mechanism that is essential for normal heart function. Our results further illustrate that organ dysfunction due to epigenetic dysregulation can be corrected by epigenetic rewiring.
Highlights
Normal developmental maturation of organ function requires precise transcriptional regulation of gene expression
We found that EED silences the slow-twitch myofiber gene program to orchestrate heart maturation by complexing with and stimulating histone deacetylases (HDACs) deacetylase activity
To identify mechanisms that account for increased H3K27ac at upregulated, EED-occupied genes in EedCKO CMs, we considered the possibility that EED biochemically regulates HDAC activity
Summary
Normal developmental maturation of organ function requires precise transcriptional regulation of gene expression This transcriptional regulation depends upon the interplay of an array of epigenetic regulators, which shape the epigenetic landscape by repositioning nucleosomes and depositing covalent modifications on histones. Since the chromatin landscape is established through a series of steps, each contingent upon normal completion of prior steps, transient disruption, through environmental mishaps or genetic mutations, might be anticipated to break the normal sequence and irreversibly impact organ development and function. Whether or not this is the case is presently unknown, and the answer has clear therapeutic implications for diseases that involve epigenetic changes
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