TGF-尾-Dependent Active Demethylation and Expression of the p15^ink4b Tumor Suppressor Are Impaired by the ZNF217/CoREST Complex

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• 作者：Gobi Thillainadesan¹ ; Jennifer  ; Mary Chitilian¹ ; Majdina Isovic¹ ; Jailal  ; Nicholas  ; George Ablack² ; Joe  ; Stephen Mymryk² ; ³ ; ⁴ ; Marc Tini² ; Joseph Torchia¹ ; ³ ; ⁴ ; ^{jtorchia@uwo.ca}
• 刊名：Molecular Cell
• 出版年：2012
• 期刊代码：111_10972765
• 类别：bio
• 出版时间：8 June, 2012
• 卷：46
• 期：5
• 页码：636-649
• 文件大小：1660 K

摘要

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Summary

In this study we examine the mechanisms of dynamic DNA methylation of the p15^ink4b tumor suppressor gene. Using conventional ChIP and ChiPseq, we identify the p15^ink4b promoter as a target for the ZNF217 oncogene, the CoREST complex, and DNMT3A. Treatment of cells with TGF-尾 triggers active demethylation involving loss of ZNF217/CoREST/DNMT3A聽and the corecruitment of SMAD2/3, CBP,聽and the DNA glycosylase TDG. Knockdown of TDG, or its functional homolog MBD4, prevents TGF-尾-dependent demethylation of p15^ink4b. DNA immunoprecipitation of 5mC and 5hmC indicates that 5mC undergoes conversion to 5hmC prior to activation of p15^ink4b. Remarkably, overexpression of ZNF217 inhibits active demethylation and expression of the p15^ink4b gene by preventing recruitment of SMAD2/3 and TDG. These findings suggest that active demethylation is essential for regulating聽a subset of TGF-尾-dependent genes. Importantly, disruption of active demethylation by the ZNF217 oncogene may be a paradigm for other oncogenic signals on DNA methylation dynamics.