Histone Methyltransferase Enhancer of Zeste Homolog 2-Mediated ABCA1 Promoter DNA Methylation Contributes to the Progression of Atherosclerosis.
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4905646?pdf=render |
| _version_ | 1818064661889679360 |
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| author | Yun-Cheng Lv Yan-Yan Tang Ping Zhang Wei Wan Feng Yao Ping-Ping He Wei Xie Zhong-Cheng Mo Jin-Feng Shi Jian-Feng Wu Juan Peng Dan Liu Francisco S Cayabyab Xi-Long Zheng Xiang-Yang Tang Xin-Ping Ouyang Chao-Ke Tang |
| author_facet | Yun-Cheng Lv Yan-Yan Tang Ping Zhang Wei Wan Feng Yao Ping-Ping He Wei Xie Zhong-Cheng Mo Jin-Feng Shi Jian-Feng Wu Juan Peng Dan Liu Francisco S Cayabyab Xi-Long Zheng Xiang-Yang Tang Xin-Ping Ouyang Chao-Ke Tang |
| author_sort | Yun-Cheng Lv |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T14:39:33Z |
| format | Article |
| id | doaj.art-cf7f10bf58ba4a7e982833dbcbc21dd3 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T14:39:33Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-cf7f10bf58ba4a7e982833dbcbc21dd32022-12-22T01:44:44ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01116e015726510.1371/journal.pone.0157265Histone Methyltransferase Enhancer of Zeste Homolog 2-Mediated ABCA1 Promoter DNA Methylation Contributes to the Progression of Atherosclerosis.Yun-Cheng LvYan-Yan TangPing ZhangWei WanFeng YaoPing-Ping HeWei XieZhong-Cheng MoJin-Feng ShiJian-Feng WuJuan PengDan LiuFrancisco S CayabyabXi-Long ZhengXiang-Yang TangXin-Ping OuyangChao-Ke TangATP-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.http://europepmc.org/articles/PMC4905646?pdf=render |
| spellingShingle | Yun-Cheng Lv Yan-Yan Tang Ping Zhang Wei Wan Feng Yao Ping-Ping He Wei Xie Zhong-Cheng Mo Jin-Feng Shi Jian-Feng Wu Juan Peng Dan Liu Francisco S Cayabyab Xi-Long Zheng Xiang-Yang Tang Xin-Ping Ouyang Chao-Ke Tang Histone Methyltransferase Enhancer of Zeste Homolog 2-Mediated ABCA1 Promoter DNA Methylation Contributes to the Progression of Atherosclerosis. PLoS ONE |
| title | Histone Methyltransferase Enhancer of Zeste Homolog 2-Mediated ABCA1 Promoter DNA Methylation Contributes to the Progression of Atherosclerosis. |
| title_full | Histone Methyltransferase Enhancer of Zeste Homolog 2-Mediated ABCA1 Promoter DNA Methylation Contributes to the Progression of Atherosclerosis. |
| title_fullStr | Histone Methyltransferase Enhancer of Zeste Homolog 2-Mediated ABCA1 Promoter DNA Methylation Contributes to the Progression of Atherosclerosis. |
| title_full_unstemmed | Histone Methyltransferase Enhancer of Zeste Homolog 2-Mediated ABCA1 Promoter DNA Methylation Contributes to the Progression of Atherosclerosis. |
| title_short | Histone Methyltransferase Enhancer of Zeste Homolog 2-Mediated ABCA1 Promoter DNA Methylation Contributes to the Progression of Atherosclerosis. |
| title_sort | histone methyltransferase enhancer of zeste homolog 2 mediated abca1 promoter dna methylation contributes to the progression of atherosclerosis |
| url | http://europepmc.org/articles/PMC4905646?pdf=render |
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