Histone Methyltransferase Enhancer of Zeste Homolog 2-Mediated ABCA1 Promoter DNA Methylation Contributes to the Progression of Atherosclerosis

Abstract

ATP-binding cassette transporter A1 (ABCA1) plays a critical role in maintaining cellular cholesterol homeostasis. The purpose of this study is to identify the molecular mechanism(s) underlying ABCA1 epigenetic modification and determine its potential impact on ABCA1 expression in macrophage-derived foam cell formation and atherosclerosis development. DNA methylation induced foam cell formation from macrophages and promoted atherosclerosis in apolipoprotein E-deficient (apoE−/−) mice. Bioinformatics analyses revealed a large CpG island (CGI) located in the promoter region of ABCA1. Histone methyltransferase enhancer of zeste homolog 2 (EZH2) downregulated ABCA1 mRNA and protein expression in THP-1 and RAW264.7 macrophage-derived foam cells. Pharmacological inhibition of DNA methyltransferase 1 (DNMT1) with 5-Aza-dC or knockdown of DNMT1 prevented the downregulation of macrophage ABCA1 expression, suggesting a role of DNA methylation in ABCA1 expression. Polycomb protein EZH2 induced DNMT1 expression and methyl-CpG-binding protein-2 (MeCP2) recruitment, and stimulated the binding of DNMT1 and MeCP2 to ABCA1 promoter, thereby promoting ABCA1 gene DNA methylation and atherosclerosis. Knockdown of DNMT1 inhibited EZH2-induced downregulation of ABCA1 in macrophages. Conversely, EZH2 overexpression stimulated DNMT1-induced ABCA1 gene promoter methylation and atherosclerosis. EZH2-induced downregulation of ABCA1 gene expression promotes foam cell formation and the development of atherosclerosis by DNA methylation of ABCA1 gene promoter.

ZRANB1 Is an EZH2 Deubiquitinase and a Potential Therapeutic Target in Breast Cancer

“…Moreover, we performed RNA sequencing (RNA-seq) analysis to compare the effect of ZRANB1 and EZH2 on global gene expression. A total of 63 genes, including known EZH2 targets or downstream genes SERPINB2 (Kim et al, 2012), PTGS2 (encoding cyclooxygenase-2) (Coward et al, 2014), ABCA1 (Lv et al, 2016), and MMP9 (Delgado-Olguín et al, 2014), were differentially expressed (49 upregulated and 14 downregulated) by at least 1.6-fold (p < 0.05) upon knockdown of either ZRANB1 or EZH2 in LM2 cells (Figures 1G and 1H; Table S1). Taken together, our data suggest that ZRANB1 is a functional regulator of EZH2.…”

Apolipoprotein A-1 Binding Protein Inhibits Inflammatory Signaling Pathways by Binding to Apolipoprotein A-1 in THP-1 Macrophages

“…4,5 Our laboratory has also demonstrated that maintaining the abundance of ABCA1 protein can effectively ensure RCT and prevent the development of atherosclerosis. [6][7][8] In addition to its role in cholesterol efflux, ABCA1 has recently been considered as an anti-inflammation I nflammation plays important roles in the development of atherosclerosis, the main cause of coronary artery disease (CAD). Accumulation of macrophages into the intima correlates with progression of atherosclerotic plaque and plaque rupture.…”

Histone methylation and vascular biology

“…Ezh2 the methyltransferase corresponding to H3K27 promoted foam cell formation and the development of atherosclerosis in ApoE −/− mice. Mechanistically, Ezh2 induced DNA methyltransferase 1 (Dnmt1) expression, methyl CpG-binding protein-2 (MeCP2) recruitment, and the binding of Dnmt1 and MeCP2 to the ATP-binding cassette transporter A1 (Abca1) promoter, thereby promoting Abca1 gene DNA methylation, which inhibited Abca1 expression and accelerated atherosclerosis [53]. Elevated low-density lipoprotein (LDL) levels are a major risk factor for atherosclerosis development.…”