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Elife. 2017 Apr 10;6. pii: e24570. doi: 10.7554/eLife.24570.

EED orchestration of heart maturation through interaction with HDACs is H3K27me3-independent.

Author information

1
Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.
2
Department of Cardiology, Boston Children's Hospital, Boston, United States.
3
Division of Hematology/Oncology, Boston Children's Hospital, Boston, United States.
4
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States.
5
Harvard Stem Cell Institute, Harvard University, Cambridge, United States.
6
Howard Hughes Medical Institute, Boston, United States.
7
Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.

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.

KEYWORDS:

cardiology; chromatin; chromosomes; developmental biology; gene regulation; genes; heart development; mouse; stem cells

PMID:
28394251
PMCID:
PMC5400508
DOI:
10.7554/eLife.24570
[Indexed for MEDLINE]
Free PMC Article

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