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

doi:10.1016/j.isci.2023.108722

Epigenetic repression of Cend1 by lysine-specific demethylase 1 is essential for murine heart development

iScience. 2023 Dec 13;27(1):108722. doi: 10.1016/j.isci.2023.108722. eCollection 2024 Jan 19.

Authors

Huahua Liu^{1

2}, Rui Zhou³, Shanshan Li¹, Jinling Dong², Yuan Fang², Yuru Luo², Hongyu Su², Baochang Lai², Lingli Liang⁴, Donghong Zhang⁵, Yanmin Zhang³, John Y-J Shyy⁶, Bin Zhou⁷, Zuyi Yuan¹, Yidong Wang⁸

Affiliations

¹ Department of Cardiology, First Affiliated Hospital, Cardiometabolic Innovation Center of Ministry of Education, Xi'an Jiaotong University, Xi'an, China.
² The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.
³ 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.
⁴ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.
⁵ Department of Cardiology, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
⁶ Division of Cardiology, Department of Medicine, University of California, San Diego, CA, USA.
⁷ Department of Genetics, Albert Einstein College of Medicine, New York, NY, USA.
⁸ 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.

Abstract

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.

Keywords: Biological sciences; Developmental biology; Natural sciences.