DNA methylation regulates α‐smooth muscle actin expression during cardiac fibroblast differentiation

• Published in: Journal of cellular physiology 2019-05, Vol.234 (5), p.7174-7185
• Main Authors: He, Yanru, Ling, Sunkai, Sun, Yuning, Sheng, Zulong, Chen, Zhongpu, Pan, Xiaodong, Ma, Genshan
• Format: Article
• Language: English
• Subjects: Actin; Actins - genetics; Actins - metabolism; Animals; cardiac fibroblast (CF) differentiation; Cell Differentiation - drug effects; Cell Proliferation; Cells, Cultured; Deoxyribonucleic acid; Differentiation; Disease Models, Animal; DNA; DNA (Cytosine-5-)-Methyltransferase 1 - genetics; DNA (Cytosine-5-)-Methyltransferase 1 - metabolism; DNA Methylation; DNMT1 protein; Epigenetics; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Fibrosis; Gene expression; Gene Expression Regulation; Growth factors; Male; Mitogen-Activated Protein Kinases - metabolism; Muscles; Myocardial infarction; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Phosphorylation; Promoter Regions, Genetic; Rats, Sprague-Dawley; Smad2 Protein - metabolism; Smad3 Protein - metabolism; Smooth muscle; Transforming growth factor; Transforming Growth Factor beta1 - pharmacology; Transforming growth factor-b1; α‐smooth muscle actin (α‐SMA)
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.27471

Cardiac fibroblast (CF) differentiation to myofibroblasts expressing α‐smooth muscle actin (α‐SMA) plays a key role in cardiac fibrosis. Therefore, a study of the mechanism regulating α‐SMA expression is a means to understanding the mechanism of fibroblast differentiation and cardiac fibrosis. Previous studies have shown that DNA methylation is associated with gene expression and is related to the development of tissue fibrosis. However, the mechanisms by which CF differentiation is regulated by DNA methylation remain unclear. Here, we explored the epigenetic regulation of α‐SMA expression and its relevance in CF differentiation. In this study, we demonstrated that α‐SMA was overexpressed and DNMT1 expression was downregulated in the infarct area after myocardial infarction. Treatment of CFs with transforming growth factor‐β1 (TGF‐β1) in vitro upregulated α‐SMA expression via epigenetic modifications. TGF‐β1 also inhibited DNMT1 expression and activity during CF differentiation. In addition, α‐SMA expression was regulated by DNMT1. Conversely, increasing DNMT1 expression levels rescued the TGF‐β1‐induced upregulation of α‐SMA expression. Finally, TGF‐β1 regulated α‐SMA expression by inhibiting the DNMT1‐mediated DNA methylation of the α‐SMA promoter. Taken together, our research showed that inhibition of the DNMT1‐mediated DNA methylation of the α‐SMA promoter plays an essential role in CF differentiation. In addition, DNMT1 may be a new target for the prevention and treatment of myocardial fibrosis. In our research, we found that α‐smooth muscle actin (α‐SMA) expression induced by TGF‐β1 was regulated by demethylation of its gene sequence through the inhibition of DNMT1 expression. In addition, the Smad and MAPK pathways are involved during this process.