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.
Highlights
It is well known that monocyte-derived macrophages are the main factors in the development of atherosclerosis, and ATP-binding cassette transporter A1 (ABCA1) is highly expressed in macrophages [1, 2]
Little is known about epigenetic modulation of ABCA1 expression, emerging evidence suggests the roles for the histone modifier, histone methyltransferase enhancer of zeste homolog 2 (EZH2), that is involved in DNA methyltransferase 1 (DNMT1) recruitment [7]
Considering the possibility that macrophage ABCA1 might be epigenetically regulated by EZH2 in the hypercholesterolemic environment, we investigated whether EZH2 altered ABCA1 gene expression, and explored the roles of epigenetic DNA regulation in the development of atherosclerosis in apoE−/− mice
Summary
It is well known that monocyte-derived macrophages are the main factors in the development of atherosclerosis, and ATP-binding cassette transporter A1 (ABCA1) is highly expressed in macrophages [1, 2]. Mice lacking ABCA1 are prone to atherosclerosis when challenged with a high-fat diet [4, 5], suggesting a critical role for ABCA1 in atheroprotection. Transcription of ABCA1 is largely controlled by its proximal promoter, which is highly conserved between mouse and human [6]. Little is known about epigenetic modulation of ABCA1 expression, emerging evidence suggests the roles for the histone modifier, histone methyltransferase enhancer of zeste homolog 2 (EZH2), that is involved in DNA methyltransferase 1 (DNMT1) recruitment [7]. It was our hypothesis that EZH2 may regulate ABCA1 gene expression by regulating DNMT1 recruitment
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