Deficiency of histone lysine methyltransferase SETDB2 in hematopoietic cells promotes vascular inflammation and accelerates atherosclerosis

• DOI: 10.1172/jci.insight.147984
• Publication Date: 2021-05-18T16:01:27Z
• Authors: Xinbo Zhang; Jonathan Sun; Alberto Canfrán-D...; Binod Aryal; George Tellides; Ying Ju Chang; Yajaira Suárez; Timothy F. Osborne; Carlos Fernández-...
• Keywords: Inflammation; Male; 0301 basic medicine; Macrophages; R; Histone-Lysine N-Methyltransferase; Atherosclerosis; Vascular biology; Plaque, Atherosclerotic; Up-Regulation; 3. Good health; Mice; 03 medical and health sciences; Medicine; Animals; Cytokines; Humans; Transcriptome; Cells, Cultured; Research Article

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. Previous studies have shown that SETDB2 is involved in innate and adaptive immunity, the proinflammatory response, and hepatic lipid metabolism. Here, we report that expression of SETDB2 is markedly upregulated in human and murine atherosclerotic lesions. Upregulation of SETDB2 was observed in proinflammatory M1 but not antiinflammatory M2 macrophages. Notably, we found that genetic deletion of SETDB2 in hematopoietic cells promoted vascular inflammation and enhanced the progression of atherosclerosis in BM transfer studies in Ldlr-knockout mice. Single-cell RNA-Seq analysis in isolated CD45+ cells from atherosclerotic plaques from mice transplanted with SETDB2-deficient BM revealed a significant increase in monocyte population and enhanced expression of genes involved in inflammation and myeloid cell recruitment. Additionally, we found that loss of SETDB2 in hematopoietic cells was associated with macrophage accumulation in atherosclerotic lesions and attenuated efferocytosis. Overall, these studies identify SETDB2 as an important inflammatory cell regulator that controls macrophage activation in atherosclerotic plaques.