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

Abstract 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‐β 1 (TGF‐β 1 ) in vitro upregulated α‐SMA expression via epigenetic modifications. TGF‐β 1 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‐β 1 ‐induced upregulation of α‐SMA expression. Finally, TGF‐β 1 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.