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

• Type of Material: Article
• Authors: Yun-Cheng Lv, University of South China; Yan-Yan Tang, Central South University; Ping Zhang, Hunan University of Science and Engineering; Wei Wan, University of South China; Feng Yao, University of South China; Ping-Ping He, University of South China; Wei Xie, University of South China; Zhong-Cheng Mo, University of South China; Jin-Feng Shi, University of South China; Jian-Feng Wu, University of South China; Juan Peng, University of South China; Dan Liu, University of South China; Francisco S. Cayabyab, University of Saskatchewan; Xi-Long Zheng, University of Calgary; Xiangyang Tang, Emory University; X-P Ouyang, University of South China; Chao-Ke Tang, University of South China
• Language: English
• Date: 2016-06-13
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Lv et al.
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0157265
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 11
• Issue: 6
• Start Page: e0157265
• End Page: e0157265
• Grant/Funding Information: The authors gratefully acknowledge the financial support from the National Natural Sciences Foundation of China (81370377 and 81300158), the Hunan Provincial Natural Science Foundation of China (14JJ2091), the Aid Program for Science and Technology Department of Human Province (2015JC3083), the Scientific Research Fund of Hunan Provincial Education Department (12C0339), the start-up funds for Ph.Ds in University of South China (2014XQD37), Zhengxiang scholar program (prof. Xiangyang Tang) of the University of South China and the construct program of the key discipline in Hunan Province.
• Keywords: DOWN-REGULATION; Multidisciplinary Sciences; APOLIPOPROTEIN-E; Atherosclerosis; Epigenetics; CELLS; KRUPPEL-LIKE FACTOR-2; Lipids; DNA methylation; Aorta; CASSETTE TRANSPORTER A1; CANCER; Cholesterol; Macrophages; Gene expression
• Research Categories: Biology, Genetics; Health Sciences, General

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.