Polycomb Repressive Complex 2 drives flow-sensitive endothelial states underlying vascular inflammation and disease
Atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality worldwide, is driven by endothelial cell inflammatory activation and counter-balanced by protective mechanosensitive transcription factors Klf2 and Klf4 (Klf2/4). Here, we identify, Polycomb Repressive Complex (PRC) 2 as a potent, therapeutically targetable determinant of vascular inflammation and ASCVD progression. PRC2 is an enzyme complex that trimethylates Histone H3 Lysine27 (H3K27me3) in gene promoter/enhancers to block gene transcription. Integrated experimental and mechanistic computational studies identified PRC2 as a central determinant of the endothelial cell state transition to an inflammatory state. PRC2 maintains the endothelial pro-inflammatory state by direct suppression of Klf2/4 transcription. PRC2 activity is elevated in endothelium from human ASCVD lesions. In murine models of acute and chronic vascular inflammation, interventional treatment with tazemetostat, an FDA-approved PRC2 inhibitor, reduced endothelial inflammatory genes, slowed disease progression and drastically improved markers of plaque stability. This study elucidates a fundamental epigenetic mechanism in vascular inflammation and identifies a potential method for treating ASCVD and related vascular inflammatory diseases.