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首页> 美国卫生研究院文献>Stem Cell Reports >YY1 Positively Regulates Transcription by Targeting Promoters and Super-Enhancers through the BAF Complex in Embryonic Stem Cells
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YY1 Positively Regulates Transcription by Targeting Promoters and Super-Enhancers through the BAF Complex in Embryonic Stem Cells

机译：YY1通过胚胎干细胞中的BAF复合物通过靶向启动子和超级增强剂来积极调节转录。

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class="head no_bottom_margin" id="sec1title">IntroductionYin Yang 1 (YY1) is the mammalian ortholog of pleiohomeotic, a transcription factor that binds Polycomb DNA response elements in Drosophila melanogaster and recruits Polycomb group (PcG) proteins to DNA (). Like certain DNA sequences (, ), transcription factors (), pre-existing histone modifications (), and non-coding RNA (), YY1 is also considered as one of the well-accepted DNA binding factors that can recruit PcG proteins to specific chromatin sites (). YY1 was originally identified as a transcriptional repressor due to its interaction with the Polycomb repressive complex 2 (), which further initiates the tri-methylation of K27 of histone 3 (H3K27me3) to repress specific genes, such as MHCIIb and MCK, during myoblast differentiation (). Moreover, YY1 has been reported to regulate cell proliferation and differentiation (), and its deficiency in mice caused peri-implantation lethality during embryonic development (). Within the B lineage of lymphocytes, YY1 has played critical roles at all stages of B cell differentiation (). Conditional deletion of Yy1 resulted in a blockage at the pro-B cell to pre-B cell stage ().Several studies also pointed out that YY1 has transcriptional activation functions independent of PcG. Findings by demonstrated that the association of YY1 with p300 resulted in histone acetylation, which caused gene activation by facilitating the binding of RNA polymerase and transcription factors to promoter regions. Studies by the Seto team revealed that YY1 recruited PRMT1 to mediate histone methylation on lysine and arginine residues, and this PRMT1-mediated histone H4-R3 methylation also induced transcriptional activation (). In addition, the association of YY1 with MDM2, PIASy, and UBC9 contributed to protein ubiquitination and sumoylation (href="#bib9" rid="bib9" class=" bibr popnode">Deng et al., 2007, href="#bib45" rid="bib45" class=" bibr popnode">Sui et al., 2004). Furthermore, href="#bib31" rid="bib31" class=" bibr popnode">Lu et al. (2013) found no significant co-occupancy between YY1 and Ezh2. They provided evidence that YY1 acts as an activator for many loci, suggesting an Ezh2-independent role of YY1 in muscle cells. Works by the Young group proposed a model wherein YY1 binds to both gene-regulatory elements and their associated RNAs, which further enhances YY1 occupancy at these elements (href="#bib41" rid="bib41" class=" bibr popnode">Sigova et al., 2015). This finding outlined a positive feedback loop that contributed to the stability of gene expression programs regulated by YY1. YY1 also plays a potential role in different cancer types. It was reported that ectopic expression of YY1 results in carcinogenesis through cell-cycle deregulation (href="#bib16" rid="bib16" class=" bibr popnode">Gordon et al., 2006). The dynamic interactions between YY1 and the cell-cycle regulators, such as CDKs, CYCLINs, pRB, and P53, frequently resulted in dysfunctional cell-cycle progression and tumorigenesis (href="#bib7" rid="bib7" class=" bibr popnode">Cicatiello et al., 2004, href="#bib35" rid="bib35" class=" bibr popnode">Parija and Das, 2003, href="#bib55" rid="bib55" class=" bibr popnode">Yakovleva et al., 2004).Although YY1 has multiple transcriptional regulation functions in various biological processes, few reports have examined the role of YY1 in pluripotency regulation. The Orkin group has classified the ESC transcriptional network into three distinct transcription modules: the core module, the PRC module, and the Myc module (href="#bib25" rid="bib25" class=" bibr popnode">Kim et al., 2010). In that regard, href="#bib50" rid="bib50" class=" bibr popnode">Vella et al. (2012) reported that YY1 did not physically interact with PcG proteins, but extended the MYC-related transcription factor network in embryonic stem cells (ESCs). They found that YY1 binding had a strong correlation with the components of the Myc module, and YY1-regulated pluripotency through gene activation rather than repression, suggesting the involvement of YY1 in Myc-related transcription network. However, the in-depth mechanisms of YY1 in pluripotency regulation, and its role in the core pluripotency network need to be better defined. In the present study, we employed immunoprecipitation (IP) for the affinity purification of YY1 protein complexes in mouse ESCs (mESCs) in combination with mass spectrometry (MS) to construct an YY1 interactome. We report the discovery of the BAF complex as a bona fide YY1 partner. Mechanistically, the BAF complex associates with YY1 to activate transcription, promote ESC proliferation, and maintain pluripotency. In the presence of the BAF complex, YY1 participates in the core pluripotent network to regulate ESC pluripotency.
机译：<！-fig ft0-> <！-fig @ position =“ anchor” mode =文章f4-> <！-fig mode =“ anchred” f5-> <！-fig / graphic | fig / alternatives / graphic mode =“ anchored” m1-> class =“ head no_bottom_margin” id =“ sec1title”>简介 Yin Yang 1（YY1）是哺乳动物多形同种异体同源基因，一种与之结合的转录因子果蝇中的Polycomb DNA反应元件，并将Polycomb组（PcG）蛋白募集到DNA（）。与某些DNA序列（，），转录因子（），预先存在的组蛋白修饰（）和非编码RNA（）一样，YY1也被认为是公认的DNA结合因子之一，可以将PcG蛋白募集到特定的染色质位点（）。 YY1最初由于其与Polycomb阻抑复合物2（）的相互作用而被鉴定为转录阻遏物，它进一步引发组蛋白3（H3K27me3）K27的三甲基化，从而抑制成肌细胞分化过程中的特定基因，例如MHCIIb和MCK （）。此外，据报道，YY1调节细胞的增殖和分化（），其在小鼠体内的缺乏导致胚胎发育过程中的着床期致死率（）。在淋巴细胞的B谱系中，YY1在B细胞分化的所有阶段都发挥了关键作用（）。有条件地删除Yy1导致pro-B细胞到pre-B细胞阶段受阻（）。多项研究还指出，YY1具有独立于PcG的转录激活功能。结果表明，YY1与p300的结合导致组蛋白乙酰化，这通过促进RNA聚合酶和转录因子与启动子区域的结合而引起基因激活。濑户团队的研究表明，YY1募集​​了PRMT1来介导赖氨酸和精氨酸残基上的组蛋白甲基化，而PRMT1介导的组蛋白H4-R3甲基化也诱导了转录激活（）。此外，YY1与MDM2，PIASy和UBC9的关联也促进了蛋白质的泛素化和磺酰化（href="#bib9" rid="bib9" class=" bibr popnode"> Deng等，2007 ，href="#bib45" rid="bib45" class=" bibr popnode"> Sui等人，2004 ）。此外，href="#bib31" rid="bib31" class=" bibr popnode"> Lu等。 （2013）发现YY1和Ezh2之间没有显着的共同占用。他们提供了证据，表明YY1是许多基因座的激活剂，表明YY1在肌肉细胞中的Ezh2独立作用。 Young小组的工作提出了一种模型，其中YY1与基因调控元件及其相关的RNA结合，从而进一步增强了YY1在这些元件上的占有率（href =“＃bib41” rid =“ bib41” class =“ bibr popnode” > Sigova et al。，2015 ）。该发现概述了一个正反馈回路，该回路有助于由YY1调节的基因表达程序的稳定性。 YY1在不同类型的癌症中也起着潜在的作用。据报道，YY1的异位表达通过细胞周期失控导致癌变（href="#bib16" rid="bib16" class=" bibr popnode"> Gordon et al。，2006 ）。 YY1与细胞周期调节剂（例如CDK，CYCLIN，pRB和P53）之间的动态相互作用经常导致功能异常的细胞周期进程和肿瘤发生（href =“＃bib7” rid =“ bib7” class =“ bibr popnode“> Cicatiello等，2004 ，href="#bib35" rid="bib35" class=" bibr popnode"> Parija and Das，2003 ，href =” ＃bib55“ rid =” bib55“ class =” bibr popnode“> Yakovleva等人，2004 ）。尽管YY1在多种生物过程中具有多种转录调控功能，但很少有报道研究YY1在多能性调控中的作用。 。 Orkin小组将ESC转录网络分为三个不同的转录模块：核心模块，PRC模块和Myc模块（href="#bib25" rid="bib25" class=" bibr popnode"> Kim等等，2010 ）。在这方面，href="#bib50" rid="bib50" class=" bibr popnode"> Vella等。 （2012）报告称，YY1并未与PcG蛋白发生物理相互作用，但扩展了胚胎干细胞（ESC）中MYC相关的转录因子网络。他们发现，YY1结合与Myc模块的组件有很强的相关性，并且YY1通过基因激活而不是阻遏来调节多能性，表明YY1参与了Myc相关的转录网络。然而，YY1在多能性调节中的深入机制及其在核心多能性网络中的作用需要得到更好的定义。在本研究中，我们采用免疫沉淀（IP）与质谱（MS）结合用于小鼠ESC（mESC）中YY1蛋白复合物的亲和纯化，以构建YY1相互作用组。我们报告发现，BAF复合体是真正的YY1合作伙伴。从机理上讲，BAF复合物与YY1结合以激活转录，促进ESC增殖，并保持多能性。在存在BAF复合体的情况下，YY1参与核心多能网络以调节ESC多能性。

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