Deficiency of histone lysine methyltransferase SETDB2 in hematopoietic cells promotes vascular inflammation and accelerates atherosclerosis
Xinbo Zhang, Jonathan Sun, Alberto Canfrán-Duque, Binod Aryal, George Tellides, Ying Ju Chang, Yajaira Suárez, Timothy F. Osborne, Carlos Fernández-Hernando
Xinbo Zhang, Jonathan Sun, Alberto Canfrán-Duque, Binod Aryal, George Tellides, Ying Ju Chang, Yajaira Suárez, Timothy F. Osborne, Carlos Fernández-Hernando
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Research Article Inflammation Vascular biology

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

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. 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.

Authors

Xinbo Zhang, Jonathan Sun, Alberto Canfrán-Duque, Binod Aryal, George Tellides, Ying Ju Chang, Yajaira Suárez, Timothy F. Osborne, Carlos Fernández-Hernando

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Figure 1

SETDB2 is the most upregulated histone methyltransferase in classically activated macrophages.

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SETDB2 is the most upregulated histone methyltransferase in classically ...
(A and B) Heatmaps representing expression (rlog-transformed values) of genes differentially expressed in WT macrophages treated without or with LPS at 4 (A) and 12 (B) hours. (C) qRT-PCR analysis of Setdb2 expression in BM-derived macrophages (BMDM) from WT mice treated with LPS (classical macrophages) or IL-4 (alternative macrophages) for 12 hours. Data represent the mean ± SEM of relative expression levels normalized to control. **P < 0.01. (D) Western blot analysis of SETDB2 in BMDM from WT and Setdb2GT mice treated with LPS (classical macrophages) or IL-4 (alternative macrophages) for 24 hours. HSP90 was used as a loading control. Quantification represents the mean ± SEM of relative expression levels normalized to control. *P < 0.05, **P < 0.01. (E) qRT-PCR analysis of Setdb2 expression in BMDM from WT mice treated with IFN-γ (5 ng/ml) and IFN-β (10 ng/ml) for 12 hours. Data represent the mean ± SEM of relative expression levels normalized to control. **P < 0.01, ***P < 0.001, ****P < 0.0001. (F) RNA-Seq analysis of Setdb2 expression in mouse peritoneal macrophages from Ldlr–/– mice fed a chow diet or Western diet for 12 weeks. Data are shown in representative counts from 3 independent experiments. Data were analyzed by 1-way ANOVA and Tukey’s post hoc test (C–E) or unpaired 2-tailed Student’s t test (F).