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PTEN 通过调节 DNMT3 来调控非 CG 甲基化从而调节心肌细胞分化。

Pten Regulates Cardiomyocyte Differentiation by Modulating Non-CG Methylation via Dnmt3.

机构信息

CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.

National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan, 250001, China.

出版信息

Adv Sci (Weinh). 2021 Sep;8(17):e2100849. doi: 10.1002/advs.202100849. Epub 2021 Jul 11.

DOI:10.1002/advs.202100849
PMID:34247447
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8425920/
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.

摘要

心肌细胞分化的调控是心脏发育和再生医学的一个基本方面。PTEN 在胚胎发育过程中发挥重要作用。然而，其在心肌细胞分化中的作用尚不清楚。本研究提出了一种从小鼠胚胎干细胞（ESCs）中诱导心肌细胞分化的低成本方案，结果表明 Pten 缺失强烈抑制心肌细胞分化。转录组分析表明，一系列心肌细胞标记基因在 Pten 心肌细胞中的表达下调。Pten 缺失通过 AKT/FoxO3a 通路诱导 Dnmt3b 的表达，并调节一系列印迹基因的表达，包括 Igf2。Dnmt3l 和 Dnmt3b 的双敲除可挽救 Pten ESC 心肌细胞分化的缺陷。通过全基因组亚硫酸氢盐测序分析野生型和 Pten 胚状体和心肌细胞的 DNA 甲基组。Pten 缺失在心肌细胞分化过程中显著促进基因组 DNA 的非 CG（CHG 和 CHH）甲基化水平，并且 Pten 心肌细胞中的心肌细胞基因和 Igf2 的非 CG 甲基化水平增加。Igf2 或 Igf1r 缺失也通过 MAPK/ERK 信号通路抑制心肌细胞分化，IGF2 补充部分挽救了心肌细胞分化。最后，生成了 Pten 条件性敲除小鼠，并在体内验证了 PTEN 在心肌细胞分化中的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6500/8425920/cca23a92528c/ADVS-8-2100849-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6500/8425920/ce5ecd584318/ADVS-8-2100849-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6500/8425920/36e81c2fec8a/ADVS-8-2100849-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6500/8425920/15a98be1d837/ADVS-8-2100849-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6500/8425920/cca23a92528c/ADVS-8-2100849-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6500/8425920/34d4c1b61093/ADVS-8-2100849-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6500/8425920/d47536f83a5e/ADVS-8-2100849-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6500/8425920/2ebd55bd46f2/ADVS-8-2100849-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6500/8425920/b9a92bbb3d5f/ADVS-8-2100849-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6500/8425920/ce5ecd584318/ADVS-8-2100849-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6500/8425920/36e81c2fec8a/ADVS-8-2100849-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6500/8425920/15a98be1d837/ADVS-8-2100849-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6500/8425920/cca23a92528c/ADVS-8-2100849-g003.jpg

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