EED orchestration of heart maturation through interaction with HDACs is H3K27me3-independent
Shanshan Ai,
Yong Peng,
Chen Li,
Fei Gu,
Xianhong Yu,
Yanzhu Yue,
Qing Ma,
Jinghai Chen,
Zhiqiang Lin,
Pingzhu Zhou,
Huafeng Xie,
Terence W Prendiville,
Wen Zheng,
Yuli Liu,
Stuart H Orkin,
Da-Zhi Wang,
Jia Yu,
William T Pu,
Aibin He
Affiliations
Shanshan Ai
Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China
Yong Peng
Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China
Chen Li
Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China
Fei Gu
Department of Cardiology, Boston Children’s Hospital, Boston, United States
Xianhong Yu
Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China
Yanzhu Yue
Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China
Qing Ma
Department of Cardiology, Boston Children’s Hospital, Boston, United States
Jinghai Chen
Department of Cardiology, Boston Children’s Hospital, Boston, United States
Zhiqiang Lin
Department of Cardiology, Boston Children’s Hospital, Boston, United States
Pingzhu Zhou
Department of Cardiology, Boston Children’s Hospital, Boston, United States
Huafeng Xie
Division of Hematology/Oncology, Boston Children’s Hospital, Boston, United States; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States
Terence W Prendiville
Department of Cardiology, Boston Children’s Hospital, Boston, United States
Wen Zheng
Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China
Yuli Liu
Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China
Stuart H Orkin
Division of Hematology/Oncology, Boston Children’s Hospital, Boston, United States; Harvard Stem Cell Institute, Harvard University, Cambridge, United States; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States; Howard Hughes Medical Institute, Boston, United States
Da-Zhi Wang
Department of Cardiology, Boston Children’s Hospital, Boston, United States; Harvard Stem Cell Institute, Harvard University, Cambridge, United States
Jia Yu
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
Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China
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.
