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Cell Dis:厦门大学刘文课题组发表甲基化修饰调控分子机制

摘要 : 2017年10月19日,国际学术权威刊物自然出版集团旗下子刊《Cell Discovery》杂志在线发表了厦门大学药学院刘文教授课题组的研究论文“Methylation of transcription factor YY2 regulates its transcriptional activity and cell proliferation”。

2017年10月19日,国际学术权威刊物自然出版集团旗下子刊《Cell Discovery》杂志在线发表了厦门大学药学院刘文教授课题组的研究论文“Methylation of transcription factor YY2 regulates its transcriptional activity and cell proliferation”。研究成果揭示了转录因子YY2的首个甲基化修饰调控的分子机制和功能。吴晓男助理教授、在读博士研究生石涛涛、何耀辉和硕士研究生王绯绯为论文共同第一作者,刘文教授为论文通讯作者。

甲基化酶和去甲基化酶通过对组蛋白动态修饰调控基因转录是表观遗传学“组蛋白密码子学说”的核心之一。同时,大量的研究表明甲基化酶和去甲基化酶也能作用于非组蛋白底物。本论文选择以YY2为代表的转录因子为研究对象,研究YY2受甲基化修饰调控的分子机制并探讨该机制在细胞中的功能。

YY2是锌指结构域转录因子YY1基因在进化中转座产生的一个同源基因,其氨基酸序列上与YY1具有56%的相同性,两者锌指结构域尤其相似,通过与DNA结合,兼具激活和抑制基因转录功能。YY2的DNA结合活性与功能是如何被调控的还完全不清楚。本论文发现:YY2蛋白在其赖氨酸247位(K247)受到甲基化酶SET7/9和去甲基化酶LSD1的动态调控。SET7/9介导的K247单甲基化修饰在体外和细胞内可以抑制YY2的DNA结合活性。我们通过对YY2、SET7/9和LSD1的敲除细胞的转录组测序发现了一个YY2与SET7/9正向调控的基因群体,该群基因同时受到LSD1的负向调控,依赖于K247位点甲基化修饰,参与细胞增殖调控功能。在肿瘤细胞中K247位点附近的氨基酸突变会改变该位点的甲基化水平、DNA结合活性及其调控的基因转录。本论文首次揭示了转录因子YY2的甲基化修饰调控机制,并阐述以YY2赖氨酸甲基化修饰为中心的表观遗传调控网络,拓展“非组蛋白密码子”的研究。研究工作是刘文教授课题组在“非组蛋白密码子”领域又一成果。

原文链接:

Methylation of transcription factor YY2 regulates its transcriptional activity and cell proliferation

原文摘要:

 

Yin Yang 1 (YY1) is a multifunctional DNA-binding transcription factor shown to be critical in a variety of biological processes, and its activity and function have been shown to be regulated by multitude of mechanisms, which include but are not limited to post-translational modifications (PTMs), its associated proteins and cellular localization. YY2, the paralog of YY1 in mouse and human, has been proposed to function redundantly or oppositely in a context-specific manner compared with YY1. Despite its functional importance, how YY2’s DNA-binding activity and function are regulated, particularly by PTMs, remains completely unknown. Here we report the first PTM with functional characterization on YY2, namely lysine 247 monomethylation (K247me1), which was found to be dynamically regulated by SET7/9 and LSD1 both in vitro and in cultured cells. Functional study revealed that SET7/9-mediated YY2 methylation regulated its DNA-binding activityin vitro and in association with chromatin examined by chromatin immunoprecipitation coupled with sequencing (ChIP-seq) in cultured cells. Knockout of YY2, SET7/9 or LSD1 by CRISPR (clustered, regularly interspaced, short palindromic repeats)/Cas9-mediated gene editing followed by RNA sequencing (RNA-seq) revealed that a subset of genes was positively regulated by YY2 and SET7/9, but negatively regulated by LSD1, which were enriched with genes involved in cell proliferation regulation. importantly, YY2-regulated gene transcription, cell proliferation and tumor growth were dependent, at least partially, on YY2 K247 methylation. Finally, somatic mutations on YY2 found in cancer, which are in close proximity to K247, altered its methylation, DNA-binding activity and gene transcription it controls. Our findings revealed the first PTM with functional implications imposed on YY2 protein, and linked YY2 methylation with its biological functions.

来源: Cell Discovery 浏览次数:0

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