Transcriptional repression by non-canonical EED stimulation of histone deacetylase activity is required for heart maturation independently of H3K27me3 [ChIP-seq]

Through H3K27me3 and H3K27ac ChIP-seq and microarray data in wile-tpye (WT) and EED-knockout (CKO) mouse cardiomyocytes, we unexpectedly uncovered a novel mechanism of PRC2-mediated gene repression. EED inactivation in the postnatal heart (EEDCKO) caused progressive, lethal dilated cardiomyopathy, with upregulation of components of the slow-twitch muscle gene program. Surprisingly, upregulation of these genes was not associated with their loss of H3K27me3, but rather with their gain of H3K27 acetylation (H3K27ac), an activating histone mark. Moreover, re-expression of EED in juvenile hearts rescued heart function and normalized H3K27ac, but not H3K27me3. Overall design: RNA-seq and Profile H3K27ac, H3K27me3, EED and HDAC2 occupancy in isolated adult cardiomyocytes from 2-month old mice, Wildtype (WT) cardiac conditional EED Knockout (CKO) and CKO injected with AAV9 expressing luciferase or HDAC1/2.