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Dual functions of Tetl in transcriptional regulation in mouse embryonic stem cells

机译：Tetl在小鼠胚胎干细胞转录调控中的双重功能

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摘要

Epigenetic modification of the mammalian genome by DNA methy-lation (5-methylcytosine) has a profound impact on chromatin structure, gene expression and maintenance of cellular identity. The recent demonstration that members of the Ten-eleven trans-location (Tet) family of proteins can convert 5-methylcytosine to 5-hydroxymethylcytosine raised the possibility that Tet proteins are capable of establishing a distinct epigenetic state. We have recently demonstrated that Tet1 is specifically expressed in murine embryonic stem (ES) cells and is required for ES cell maintenance2. Using chromatin immunoprecipitation coupled with high-throughput DNA sequencing, here we show in mouse ES cells that Tet1 is preferentially bound to CpG-rich sequences at promoters of both transcriptionally active and Polycomb-repressed genes. Despite an increase in levels of DNA methylation at many Tet1-binding sites, Tetl depletion does not lead to downregulation of all the Tet1 targets. Interestingly, although Tet1-mediated promoter hypomethylation is required for maintaining the expression of a group of transcriptionally active genes, it is also involved in repression of Polycomb-targeted developmental regulators. Tetl contributes to silencing of this group of genes by facilitating recruitment of PRC2 to CpG-rich gene promoters. Thus, our study not only establishes a role for Tetl in modulating DNA methylation levels at CpG-rich promoters, but also reveals a dual function of Tet1 in promoting transcription of pluripotency factors as well as participating in the repression of Polycomb-targeted developmental regulators.
机译：DNA甲基化（5-甲基胞嘧啶）对哺乳动物基因组的表观遗传修饰对染色质结构，基因表达和维持细胞身份具有深远的影响。最近的证明，蛋白质的十一十一易位（Tet）家族的成员可以将5-甲基胞嘧啶转化为5-羟甲基胞嘧啶，这增加了Tet蛋白能够建立独特的表观遗传状态的可能性。我们最近证明，Tet1在鼠胚胎干（ES）细胞中特异性表达，并且是ES细胞维持所必需的2。使用染色质免疫沉淀与高通量DNA测序相结合，在这里我们在小鼠ES细胞中显示Tet1在转录活性和Polycomb抑制基因的启动子上优先结合到富含CpG的序列上。尽管许多Tet1结合位点的DNA甲基化水平增加，但Tetl耗竭并不会导致所有Tet1靶标的下调。有趣的是，尽管Tet1介导的启动子低甲基化对于维持一组转录活性基因的表达是必需的，但它也参与了针对Polycomb的发育调控因子的抑制。 Tetl通过促进将PRC2募集到富含CpG的基因启动子来促进该基因的沉默。因此，我们的研究不仅确定了Tetl在调节富含CpG的启动子的DNA甲基化水平中的作用，而且还揭示了Tet1在促进多能性因子转录以及参与针对Polycomb的发育调节因子的阻抑中的双重功能。

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  • 来源
    《Nature》 |2011年第7347期|p.389-393|共5页
  • 作者

    Hao Wu; Ana C. DAlessio; Shinsuke Ito; Kai Xia; Zhibin Wang; Kairong Cui; Keji Zhao; Yi Eve Sun; Yi Zhang;

  • 作者单位

    Cardiovascular Research Centre, Massachusetts General Hospital, 185 Cambridge Street Boston, Massachusetts 02114, USA and Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA;

    Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA;

    Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA;

    Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA;

    Laboratory of Human Environmental Epigenomes, Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21025,USA;

    Laboratory of Molecular Immunology, The National Heart Lung, and Blood Institute, NIH, Bethesda, Maryland 20892, USA;

    Laboratory of Molecular Immunology, The National Heart Lung, and Blood Institute, NIH, Bethesda, Maryland 20892, USA;

    Departments of Molecular & Medical Pharmacology and Psychiatry & Biobehavioral Sciences, IDDRC at Semel Institute of Neuroscience and Human Behavior, UCLA David Geffen School of Medicine, Los Angeles,California, 90095, USA;

    Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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