Epigenetic Regulation of Phenotypic Plasticity of Vascular Smooth Muscle Cells

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Vascular smooth muscle cells (SMCs) are not terminally differentiated and have phenotypic plasticity: differentiated, contractile SMCs can undergo dedifferentiation and become synthetic and proliferative, and vice versa. Myocardin, a transcriptional coactivator of serum response factor (SRF), controls the expression of SMC contractile proteins and microRNAs (miRs) to promote SMC differentiation and inhibit cell proliferation. Many factors including hormones, growth factors and cytokines regulate SMC plasticity, but how they trigger intracellular signaling to confer phenotypic switching is poorly understood. Evidence suggests that epigenetic modification participates in SMC phenotype regulation. DNA methylation, for example, inhibits myocardin gene expression. DNA methylation and demethylation are catalyzed by methyltransferases (DNMT1, 3A, 3B) and ten-eleven translocation (TET1, 2, 3) enzymes, respectively. Myocardin is associated with demethylation of its target genes, in which TET2 binds to CArG boxes in the promoters. However, the exact mechanisms underlying epigenetic regulation of SMC phenotypes remain largely unknown. Rationale and hypothesis. Our preliminary results showed a role for DNA methylation in myocardin expression and functions. Our previous findings also revealed myocardin induction of miR-1 expression and inhibition of cell proliferation. Therefore, we hypothesize that myocardin gene methylation and demethylation determines myocardin gene expression and that myocardin also induces DNA demethylation of its target genes, driving SMC differentiation and inhibiting cell proliferation. Objectives. To test the above hypotheses, we set up two aims over 5 years: 1) Investigate the roles for myocardin gene methylation and demethylation in SMC phenotypic plasticity. We expect to discover or reveal the specific DNMTs and TETs that dictate the DNA methylation level of the myocardin gene, contributing to the regulation of SMC phenotypic plasticity. 2) Determine how myocardin modulates DNA methylation of its target genes, including SM contractile proteins and miRs. We expect to reveal myocardin induction of demethylation of its target genes, such as SM contractile proteins and miRs, and the underlying mechanisms. Significance. Our studies will uncover a novel epigenetic mechanism underlying SMC phenotypic plasticity, representing a major advancement in vascular biology.