Epigenetic regulation of gene expression in vascular smooth muscle cells

Abstract

Vascular smooth muscle cell (VSMC) phenotypic switching is a hallmark of atherosclerosis, UK’s main cause of death. During phenotypic switching, the gene expression profile of VSMCs changes dramatically. The resulting loss of contractility and increased migration, proliferation and secretion of proinflammatory cytokines contribute directly to atherosclerotic lesion growth and vascular inflammation. We study how regulation of gene expression by epigenetic mechanisms impact on VSMC phenotypic switching. Using a stem cell model we identified methylation of Histone H3 Lysine 9 (H3K9) as a regulatory pathway of VSMC gene expression. Subsequent studies using ex vivo and cultured VSMCs isolated from mouse aorta demonstrated that contractile VSMC genes display increased levels of methylated H3K9 during in vitro induced phenotypic switching. We have mapped the levels of methylated H3K9 genome-wide and find that this repressive epigenetic mark is also found at the promoters of inflammation-associated genes, including a subset of matrix metallo proteases in VSMCs. Using a small molecule inhibitor of the G9a/GLP methyl transferases, we furthermore demonstrated that this pathway is functionally relevant for regulating gene expression in VSMC. Our studies demonstrate that H3K9 methylation represses the expression of disease-related genes in VSMCs and suggest that this pathway might function to prevent unsolicited vascular inflammation.