Open AccessPten Regulates Cardiomyocyte Differentiation by Modulating Non‐CG Methylation via Dnmt3
Author(s) -
Wang Wuming,
Lu Gang,
Liu HongBin,
Xiong Zhiqiang,
Leung HoDuen,
Cao Ruican,
Pang Alan LapYin,
Su Xianwei,
Law Patrick Wai Nok,
Zhao Zhiju,
Chen ZiJiang,
Chan WaiYee
Publication year - 2021
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202100849
Subject(s) - pten , biology , dna methylation , embryonic stem cell , microbiology and biotechnology , dnmt3b , cellular differentiation , conditional gene knockout , transcriptome , embryoid body , pi3k/akt/mtor pathway , signal transduction , induced pluripotent stem cell , gene expression , genetics , gene , phenotype
The regulation of cardiomyocyte differentiation is a fundamental aspect of cardiac development and regenerative medicine. PTEN plays important roles during embryonic development. However, its role in cardiomyocyte differentiation remains unknown. In this study, a low‐cost protocol for cardiomyocyte differentiation from mouse embryonic stem cells (ESCs) is presented and it is shown that Pten deletion potently suppresses cardiomyocyte differentiation. Transcriptome analysis shows that the expression of a series of cardiomyocyte marker genes is downregulated in Pten −/− cardiomyocytes. Pten ablation induces Dnmt3b expression via the AKT/FoxO3a pathway and regulates the expression of a series of imprinted genes, including Igf2 . Double knockout of Dnmt3l and Dnmt3b rescues the deficiency of cardiomyocyte differentiation of Pten −/− ESCs. The DNA methylomes from wild‐type and Pten −/− embryoid bodies and cardiomyocytes are analyzed by whole‐genome bisulfite sequencing. Pten deletion significantly promotes the non‐CG (CHG and CHH) methylation levels of genomic DNA during cardiomyocyte differentiation, and the non‐CG methylation levels of cardiomyocyte genes and Igf2 are increased in Pten −/− cardiomyocytes. Igf2 or Igf1r deletion also suppresses cardiomyocyte differentiation through the MAPK/ERK signaling pathway, and IGF2 supplementation partially rescues the cardiomyocyte differentiation. Finally, Pten conditional knockout mice are generated and the role of PTEN in cardiomyocyte differentiation is verified in vivo.