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Early-stage epigenetic modification during somatic cell reprogramming by Parpl and Tet2

机译：Parpl和Tet2在体细胞重编程过程中的早期表观遗传修饰

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摘要

Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by using the pluripotency factors Oct4, Sox2, Klf4 and c-Myc (together referred to as OSKM). iPSC reprogramming erases somatic epigenetic signatures—as typified by DNA methyla-tion or histone modification at silent pluripotency loci—and establishes alternative epigenetic marks of embryonic stem cells (ESCs)2. Here we describe an early and essential stage of somatic cell reprogramming, preceding the induction of transcription at endogenous pluripotency loci such as Nanog and Esrrb. By day 4 after transduction with OSKM, two epigenetic modification factors necessary for iPSC generation, namely poly(ADP-ribose) polymerase-1 (Parpl) and ten-eleven translocation-2 (Tet2), are recruited to the Nanog and Esrrb loci. These epigenetic modification factors seem to have complementary roles in the establishment of early epigenetic marks during somatic cell reprogramming: Parpl functions in the regulation of 5-methylcytosine (5mC) modification, whereas Tet2 is essential for the early generation of 5-hydroxymethylcytosine (5hmC) by the oxidation of 5mC (refs 3,4). Although 5hmC has been proposed to serve primarily as an intermediate in 5mC demethylation to cytosine in certain contexts5"7, our data, and also studies of Tet2-mutant human tumour cells8, argue in favour of a role for 5hmC as an epigenetic mark distinct from 5mC. Consistent with this, Parpl and Tet2 are each needed for the early establishment of histone modifications that typify an activated chromatin state at pluripotency loci, whereas Parpl induction further promotes accessibility to the Oct4 reprogramming factor. These findings suggest that Parpl and Tet2 contribute to an epigenetic program that directs subsequent transcriptional induction at pluripotency loci during somatic cell reprogramming.%体细胞被“Yamanaka因子”重新编程为“诱导rn多能干”(iPS)细胞的早期“外成机制”尚不清rn楚。Asa Abeliovich及其同事发现，到细胞重rn新编程的第四天，两个DNA修饰酶Parp1和rnTet2被吸收到内生多能位点(如Nanog和Esrrb)rn上，导致被改变的胞嘧啶盐基5mC和5hmC的rn局部积累。Parp 1和Tet2通过单独的、但重叠rn的机制发挥作用，来调控5hmC/5mC比率，后rn者与转录活性相关。这些发现说明5hmC在rn“外成重新编程”过程中还有其他作用。
机译：通过使用多能性因子Oct4，Sox2，Klf4和c-Myc（统称为OSKM），可以将体细胞重编程为诱导性多能干细胞（iPSC）。 iPSC重编程可消除体细胞表观遗传学特征（以沉默多能位点处的DNA甲基化或组蛋白修饰为代表），并建立胚胎干细胞（ESC）2的替代表观遗传学标记。在这里，我们描述了在内源多能性位点（例如Nanog和Esrrb）诱导转录之前，体细胞重编程的早期和必要阶段。在用OSKM转导后的第4天，iPSC生成所需的两个表观遗传修饰因子，即聚（ADP-核糖）聚合酶-1（Parp1）和十一个11易位2（Tet2），被募集到Nanog和Esrrb基因座。这些表观遗传修饰因子似乎在体细胞重编程过程中的早期表观遗传标记的建立中具有互补的作用：Parpl在调节5-甲基胞嘧啶（5mC）修饰中起作用，而Tet2对于5-羟甲基胞嘧啶（5hmC）的早期生成至关重要通过5mC的氧化（参考3,4）。尽管有人提出在某些情况下5hmC主要用作5mC胞嘧啶去甲基化的中间体5“ 7，但我们的数据以及Tet2突变人类肿瘤细胞的研究8都主张5hmC作为不同于与此相符，Parpl和Tet2分别是早期建立组蛋白修饰所需要的，组蛋白修饰代表了多能性位点处激活的染色质状态，而Parpl的诱导进一步促进了对Oct4重编程因子的可及性。一个表观遗传程序，用于在体细胞重编程期间指导多能性位点的后续转录诱导。％体细胞被“ Yamanaka因子”重新编程为“诱导rn多能干”（iPS）细胞的早期“外成机制”尚不清rn楚。 Asa Abeliovich及其同事发现，到细胞重rn新编程的第四天，两个DNA修饰酶Parp1和rnTet2被吸收到内生多能位点（如Nanog和Esrrb）rn上，导致被改变的胞胞溶解盐基5mC和5hmC的rn积累。重新编程”过程中还有其他作用。

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  • 来源
    《Nature》 |2012年第7413期|p.652-655A2|共5页
  • 作者

    Claudia A. Doege; Keiichi Inoue; Toru Yamashita; David B. Rhee; Skylar Travis; Ryousuke Fujita; Paolo Guarnieri; Govind Bhagat; William B. Vanti; Alan Shih; Ross L. Levine; Sara Nik; Emily I. Chen; Asa Abeliovich;

  • 作者单位

    Departments of Pathology and Cell Biology and Neurology,Taub Institute for Aging,Columbia University,New York,New York 10032,USA;

    Departments of Pathology and Cell Biology and Neurology,Taub Institute for Aging,Columbia University,New York,New York 10032,USA;

    Departments of Pathology and Cell Biology and Neurology,Taub Institute for Aging,Columbia University,New York,New York 10032,USA;

    Departments of Pathology and Cell Biology and Neurology,Taub Institute for Aging,Columbia University,New York,New York 10032,USA;

    Departments of Pathology and Cell Biology and Neurology,Taub Institute for Aging,Columbia University,New York,New York 10032,USA;

    Departments of Pathology and Cell Biology and Neurology,Taub Institute for Aging,Columbia University,New York,New York 10032,USA;

    Biomedical Informatics Shared Resources,Bioinformatics Division,Columbia University,New York,New York 10032,USA,Herbert Irving Comprehensive Cancer Center,Columbia University,New York,New York 10032,USA;

    Departments of Pathology and Cell Biology and Neurology,Taub Institute for Aging,Columbia University,New York,New York 10032,USA,Herbert Irving Comprehensive Cancer Center,Columbia University,New York,New York 10032,USA;

    Departments of Pathology and Cell Biology and Neurology,Taub Institute for Aging,Columbia University,New York,New York 10032,USA;

    Human Oncology and Pathogenesis Program,Memorial Sloan Kettering Cancer Center,New York,New York 10016,USA;

    Human Oncology and Pathogenesis Program,Memorial Sloan Kettering Cancer Center,New York,New York 10016,USA;

    Department of Pharmacological Sciences,Stony Brook University,Stony Brook,New York 11794,USA;

    Department of Pharmacological Sciences,Stony Brook University,Stony Brook,New York 11794,USA,Stony Brook University Proteomics Center,School Of Medicine,Stony Brook,New York 11794,USA;

    Departments of Pathology and Cell Biology and Neurology,Taub Institute for Aging,Columbia University,New York,New York 10032,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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