Pten Regulates Cardiomyocyte Differentiation by Modulating Non‐CG Methylation via Dnmt3
Open Access
- 11 July 2021
- journal article
- research article
- Published by Wiley in Advanced Science
- Vol. 8 (17), 2100849
- https://doi.org/10.1002/advs.202100849
Abstract
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.This publication has 60 references indexed in Scilit:
- A Cotton Annexin Protein AnxGb6 Regulates Fiber Elongation through Its Interaction with Actin 1PLOS ONE, 2013
- Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signalingProceedings of the National Academy of Sciences of the United States of America, 2012
- Base-Resolution Analyses of Sequence and Parent-of-Origin Dependent DNA Methylation in the Mouse GenomeCell, 2012
- Hand2 function in second heart field progenitors is essential for cardiogenesisDevelopmental Biology, 2011
- Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined FactorsCell, 2010
- Human DNA methylomes at base resolution show widespread epigenomic differencesNature, 2009
- Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylationNature, 2007
- Canonical Wnt signaling is a positive regulator of mammalian cardiac progenitorsProceedings of the National Academy of Sciences of the United States of America, 2007
- Phosphorylation of the PTEN Tail Acts as an Inhibitory Switch by Preventing Its Recruitment into a Protein ComplexOnline Journal of Public Health Informatics, 2001
- High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in miceCurrent Biology, 1998