title: EED orchestration of heart maturation through interaction with HDACs is H3K27me3-independent.
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 EedCKOwas 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 EedCKOheart 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.
authors.affiliation: Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Ai
authors.affiliation: Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, United States.
authors.forename: Fei
authors.initials: F
authors.lastname: Gu
authors.affiliation: Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.
authors.forename: Xianhong
authors.initials: X
authors.lastname: Yu
authors.affiliation: Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.
authors.forename: Yanzhu
authors.initials: Y
authors.lastname: Yue
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, United States.
authors.forename: Jinghai
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, United States.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, United States.
authors.forename: Pingzhu
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, United States.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Xie
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, United States.
authors.forename: Terence W
authors.initials: TW
authors.lastname: Prendiville
authors.affiliation: Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.
authors.forename: Yuli
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, United States.|Harvard Stem Cell Institute, Harvard University, Cambridge, United States.
authors.forename: Da-Zhi
authors.initials: DZ
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, United States.|Harvard Stem Cell Institute, Harvard University, Cambridge, United States.
authors.forename: William T
authors.identifier: 0000-0002-4551-8079
authors.initials: WT
authors.lastname: Pu
authors.affiliation: Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.
authors.forename: Aibin
authors.identifier: 0000-0002-3489-2305
authors.initials: A
authors.lastname: He
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D063185:Epigenetic Repression; D006321:Heart / Q000196:embryology*; D006655:Histone Deacetylases / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000502:physiology; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
chemical_list: D063151:Polycomb Repressive Complex 2; D006655:Histone Deacetylases
keywords: cardiology; chromatin; chromosomes; developmental biology; gene regulation; genes; heart development; mouse; stem cells