Epigenetic repression of Cend1 by lysine-specific demethylase 1 is essential for murine heart development
Huahua Liu,
Rui Zhou,
Shanshan Li,
Jinling Dong,
Yuan Fang,
Yuru Luo,
Hongyu Su,
Baochang Lai,
Lingli Liang,
Donghong Zhang,
Yanmin Zhang,
John Y-J. Shyy,
Bin Zhou,
Zuyi Yuan,
Yidong Wang
Affiliations
Huahua Liu
Department of Cardiology, First Affiliated Hospital, Cardiometabolic Innovation Center of Ministry of Education, Xi’an Jiaotong University, Xi’an, China; The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
Rui Zhou
Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Shaanxi Institute for Pediatric Diseases, Xi’an Children’s Hospital, Affiliated Children’s Hospital, Xi’an Jiaotong University, Xi’an, China
Shanshan Li
Department of Cardiology, First Affiliated Hospital, Cardiometabolic Innovation Center of Ministry of Education, Xi’an Jiaotong University, Xi’an, China
Jinling Dong
The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
Yuan Fang
The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
Yuru Luo
The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
Hongyu Su
The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
Baochang Lai
The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
Lingli Liang
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
Donghong Zhang
Department of Cardiology, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
Yanmin Zhang
Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Shaanxi Institute for Pediatric Diseases, Xi’an Children’s Hospital, Affiliated Children’s Hospital, Xi’an Jiaotong University, Xi’an, China
John Y-J. Shyy
Division of Cardiology, Department of Medicine, University of California, San Diego, CA, USA
Bin Zhou
Department of Genetics, Albert Einstein College of Medicine, New York, NY, USA
Zuyi Yuan
Department of Cardiology, First Affiliated Hospital, Cardiometabolic Innovation Center of Ministry of Education, Xi’an Jiaotong University, Xi’an, China; Corresponding author
Yidong Wang
The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Department of Cardiology, First Affiliated Hospital, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Cardiometabolic Innovation Center of Ministry of Education, Xi’an Jiaotong University, Xi’an, China; Corresponding author
Summary: Epigenetic regulation of heart development remains incompletely understood. Here we show that LSD1, a histone demethylase, plays a crucial role in regulating cardiomyocyte proliferation during heart development. Cardiomyocyte-specific deletion of Lsd1 in mice inhibited cardiomyocyte proliferation, causing severe growth defect of embryonic and neonatal heart. In vivo RNA-seq and in vitro functional studies identified Cend1 as a target suppressed by LSD1. Lsd1 loss resulted in elevated Cend1 transcription associated with increased active histone mark H3K4me2 at Cend1 promoter. Cend1 knockdown relieved the cell-cycle arrest and proliferation defect caused by LSD1 inhibition in primary rat cardiomyocytes. Moreover, genetic deletion of Cend1 rescued cardiomyocyte proliferation defect and embryonic lethality in Lsd1 null embryos. Consistently, LSD1 promoted the cell cycle of cardiomyocytes derived from human-induced pluripotent stem cells by repressing CEND1. Together, these findings reveal an epigenetic regulatory mechanism involving the LSD1-CEND1 axis that controls cardiomyocyte proliferation essential for murine heart development.
