title: Chromatin-remodelling factor Brg1 regulates myocardial proliferation and regeneration in zebrafish.
abstract: The zebrafish possesses a remarkable capacity of adult heart regeneration, but the underlying mechanisms are not well understood. Here we report that chromatin remodelling factor Brg1 is essential for adult heart regeneration. Brg1 mRNA and protein are induced during heart regeneration. Transgenic over-expression of dominant-negative Xenopus Brg1 inhibits the formation of BrdU+/Mef2C+and Tg(gata4:EGFP) cardiomyocytes, leading to severe cardiac fibrosis and compromised myocardial regeneration. RNA-seq and RNAscope analyses reveal that inhibition of Brg1 increases the expression of cyclin-dependent kinase inhibitors such as cdkn1a and cdkn1c in the myocardium after ventricular resection; and accordingly, myocardial-specific expression of dn-xBrg1 blunts myocardial proliferation and regeneration. Mechanistically, injury-induced Brg1, via its interaction with Dnmt3ab, suppresses the expression of cdkn1c by increasing the methylation level of CpG sites at the cdkn1c promoter. Taken together, our results suggest that Brg1 promotes heart regeneration by repressing cyclin-dependent kinase inhibitors partly through Dnmt3ab-dependent DNA methylation.
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing 100871, China.|Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.|State Key Laboratory of Natural and Biomimetic Drugs, Beijing 100871, China.
authors.forename: Chenglu
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing 100871, China.|Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.|State Key Laboratory of Natural and Biomimetic Drugs, Beijing 100871, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.affiliation: Biodynamic Optical Imaging Center, Peking University, Beijing 100871, China.|College of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hou
authors.affiliation: School of Life Sciences, University of Science and Technology of China, Hefei 230026, China.|Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China.
authors.forename: Congfei
authors.initials: C
authors.lastname: Xu
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing 100871, China.|Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.|State Key Laboratory of Natural and Biomimetic Drugs, Beijing 100871, China.
authors.forename: Nannan
authors.initials: N
authors.lastname: Chang
authors.affiliation: Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Beijing 100193, China.|Peking Union Medical College, Beijing 100730, China.
authors.forename: Keping
authors.initials: K
authors.lastname: Hu
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing 100871, China.|Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Aibin
authors.initials: A
authors.lastname: He
authors.affiliation: Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Luo
authors.affiliation: School of Life Sciences, University of Science and Technology of China, Hefei 230026, China.|Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jinrong
authors.initials: J
authors.lastname: Peng
authors.affiliation: Biodynamic Optical Imaging Center, Peking University, Beijing 100871, China.|College of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Fuchou
authors.initials: F
authors.lastname: Tang
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing 100871, China.|Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.|State Key Laboratory of Natural and Biomimetic Drugs, Beijing 100871, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing 100871, China.|Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.|State Key Laboratory of Natural and Biomimetic Drugs, Beijing 100871, China.
authors.forename: Jing-Wei
authors.initials: JW
authors.lastname: Xiong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D049109:Cell Proliferation; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism; D019175:DNA Methylation; D006321:Heart / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D012038:Regeneration; D015854:Up-Regulation; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050761:Cyclin-Dependent Kinase Inhibitor p57; D029961:Zebrafish Proteins; C516328:smarca4a protein, zebrafish