Epigenetic repression of Cend1 by LSD1 is essential for murine heart development
Epigenetic regulation of heart development remains incompletely understood. Here we show that lysine-specific demethylase 1 (LSD1), a histone demethylase, critically controls 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, a cell cycle repressor, as a target suppressed by LSD1. Loss of Lsd1 resulted in elevated Cend1 transcription associated with increased active histone mark H3K4me2 at the Cend1 promoter regions. Cend1 knockdown fully relieved the cell cycle arrest and proliferation defect caused by LSD1 inhibition in primary rat cardiomyocytes. Consistently, genetic deletion of Cend1 rescued cardiomyocyte proliferation defect and embryonic lethality in Lsd1 null embryos. Mechanistically, LSD1 promoted cardiomyocyte cycling and proliferation via CEND1-mediated suppression of p53 pathway. In line with the observations in mice, LSD1 promoted the cell cycle of cardiomyocytes derived from human-induced pluripotent stem cells by repressing CEND1-p53 axis. Together, these findings reveal an epigenetic regulatory mechanism consisting of the LSD1-CEND1-p53 axis that controls cardiomyocyte proliferation essential for murine heart development. Overall design: the E12.5 heart ventricles tissue of control and LSD1-CKO mouse were aqcuired for total RNA extraction. The RNA extraction method was described in manuscript.