GSE169112
Deficiency of histone lysine methyltransferase SETDB2 in hematopoietic cells promotes  vascular inflammation and accelerates atherosclerosis
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  (MF). 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. Overall design: scRNA-seq of CD45+ cells from atherosclerotic plaques of Ldlr-/- mouse transplanted with WT or Setdb2-/- bone marrow cells