Deficiency of histone lysine methyltransferase SETDB2 in hematopoietic cells promotes vascular inflammation and accelerates atherosclerosis
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ABSTRACT: Epigenetic modifications of the genome, including DNA methylation, histone methylation/acetylation and noncoding RNAs, have been reported to play a fundamental role in regulating immune response during the progression of atherosclerosis. SETDB2 is a member of the KMT1 family of lysine methyltransferases and members of this family typically methylate histone H3 Lys9 (H3K9), an epigenetic mark associated with gene silencing and previous studies have shown SETDB2 is involved in innate and adaptive immunity, the pro-inflammatory response and hepatic lipid metabolism. Here we report that the expression of SETDB2 is markedly upregulated in human and murine atherosclerotic lesions. The upregulation of SETDB2 is observed in pro-inflammatory M1, but not anti-inflammatory M2 macrophages (MΦ). Notably, we found that genetic deletion of SETDB2 in hematopoietic cells promotes vascular inflammation and enhances the progression of atherosclerosis in bone marrow transfer studies in LDLR knockout mice. Single cell RNA-Seq analysis in isolated CD45+ cells from atherosclerotic plaques from mice with SETDB2 deficient bone marrow revealed a significant increase in inflammatory macrophage population and enhanced expression of genes involved in inflammation, myeloid cell recruitment and lipid metabolism. Additionally, we found that loss of SETDB2 in hematopoietic cells is associated with macrophage accumulation in atherosclerotic lesions, macrophage proliferation and attenuated efferocytosis. Overall, these studies identify SETDB2 as an important inflammatory cell regulator that controls macrophage activation in atherosclerotic plaques.
ORGANISM(S): Mus musculus
PROVIDER: GSE169112 | GEO | 2021/03/18
REPOSITORIES: GEO
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