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首页> 外文期刊>Cell discovery. >Methylation of transcription factor YY2 regulates its transcriptional activity and cell proliferation
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Methylation of transcription factor YY2 regulates its transcriptional activity and cell proliferation

机译：转录因子YY2的甲基化调节其转录活性和细胞增殖

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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 activity in 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.
机译：阴阳1（YY1）是一种多功能的DNA结合转录因子，在多种生物过程中显示出至关重要的作用，其活性和功能已显示受多种机制的调控，这些机制包括但不限于：翻译修饰（PTM），其相关蛋白和细胞定位。已经提出，YY2在小鼠和人类中是YY1的旁系同源物，与YY1相比，它以上下文特定的方式冗余或相反地起作用。尽管具有重要的功能，但如何完全控制YY2的DNA结合活性和功能（尤其是通过PTM调节）仍然未知。在这里，我们报道了第一个在YY2上具有功能特征的PTM，即赖氨酸247单甲基化（K247me1），该蛋白在体外和培养细胞中均受到SET7 / 9和LSD1的动态调节。功能研究表明，SET7 / 9介导的YY2甲基化可在体外以及与染色质相关的DNA结合活性，而染色质通过染色质免疫沉淀结合测序（ChIP-seq）在培养的细胞中进行检测。 CRISPR（簇状，规则间隔，短回文重复）敲除YY2，SET7 / 9或LSD1 / Cas9介导的基因编辑，然后进行RNA测序（RNA-seq），揭示了一部分基因受到YY2和SET7 /的正调控。 9，但由LSD1负调控，而LSD1富含与细胞增殖调控有关的基因。重要的是，YY2调控的基因转录，细胞增殖和肿瘤生长至少部分取决于YY2 K247甲基化。最后，在癌症中发现的YY2体细胞突变与K247极为接近，从而改变了其甲基化，DNA结合活性和它控制的基因转录。我们的发现揭示了第一个对YY2蛋白具有功能含义的PTM，并将YY2甲基化与其生物学功能联系在一起。

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