GSE131212
Histone 3 Lysine 9 Dimethylation Attenuates the Vascular Smooth Muscle Cell Inflammatory Response
Vascular inflammation underlies cardiovascular disease. Vascular smooth muscle cells (VSMCs) upregulate selective genes, including matrix metalloproteinases (MMPs) and pro-inflammatory cytokines in response to local inflammation, which directly contribute to vascular disease and adverse clinical outcome. Identification of factors controlling VSMC responses to inflammation is therefore of considerable therapeutic importance. Here, we determine the role of H3K9me2, a repressive epigenetic mark that is reduced in atherosclerotic lesions, in regulating the VSMC inflammatory response. We used VSMC-lineage tracing to detect reduced H3K9me2 levels in VSMCs of arteries after injury and in atherosclerosis. Intriguingly, chromatin immunoprecipitation revealed H3K9me2 enrichment at a subset of inflammation-responsive gene promoters, including MMP3, MMP9, MMP12 and IL6, in mouse and human VSMCs. Inhibition of G9A/GLP, the primary enzymes responsible for H3K9me2, significantly potentiated inflammation-induced gene induction in vitro and in vivo without altering NFkB and MAPK signalling. Rather, reduced G9A/GLP activity enhanced inflammation-induced binding of transcription factors NFkB-p65 and cJUN to H3K9me2 target gene promoters MMP3 and IL6. Taken together, these results suggest that promoter-associated H3K9me2 directly attenuates the induction of target genes in response to inflammation in human VSMCs. This study implicates H3K9me2 in regulating the pro-inflammatory VSMC phenotype. Our findings suggest that reduced H3K9me2 in disease allows complete binding of NFkB and AP-1 transcription factors at specific inflammation-responsive genes to augment pro-inflammatory stimuli in VSMC. Since increased MMP and IL6 activity are features of vascular disease, H3K9me2-regulation may be a novel target for clinical intervention. Overall design: This submission contains a total of four samples: two replicates of H3K9me2 ChIP from ex vivo vascular smooth muscle cells, and two corresponding input samples.