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Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability

机译：胚胎致死表型揭示了TDG在维持表观遗传稳定性方面的功能

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摘要

Thymine DNA glycosylase (TDG) is a member of the uracil DNA glycosylase (UDG) superfamily of DNA repair enzymes. Owing to its ability to excise thymine when mispaired with guanine, it was proposed to act against the mutability of 5-methylcytosine (5-mC) deamination in mammalian DNA1. However, TDG was also found to interact with transcription factors, histone acetyltransferases4 and de novo DNA methyltransferases, and it has been associated with DNA demethylation in gene promoters following activation of transcription, altogether implicating an engagement in gene regulation rather than DNA repair. Here we use a mouse genetic approach to determine the biological function of this multifaceted DNA repair enzyme. We find that, unlike other DNA glycosylases, TDG is essential for embryonic development, and that this phenotype is associated with epigenetic aberrations affecting the expression of developmental genes. Fibroblasts derived from Tdg null embryos (mouse embryonic fibroblasts, MEFs) show impaired gene regulation, coincident with unbalanced histone modification and CpG methylation at promoters of affected genes. TDG associates with the promoters of such genes both in fibroblasts and in embryonic stem cells (ESCs), but epigenetic aberrations only appear upon cell lineage commitment. We show that TDG contributes to the maintenance of active and bivalent chromatin throughout cell differentiation, facilitating a proper assembly of chromatin-modifying complexes and initiating base excision repair to counter aberrant denovo methylation. We thus conclude that TDG-dependent DNA repair has evolved to provide epigenetic stability in lineage committed cells.
机译：胸腺嘧啶DNA糖基化酶（TDG）是DNA修复酶的尿嘧啶DNA糖基化酶（UDG）超家族的成员。由于其与鸟嘌呤错配时可切除胸腺嘧啶的能力，有人提出要对哺乳动物DNA1中5-甲基胞嘧啶（5-mC）脱氨基的变异性起作用。但是，还发现TDG与转录因子，组蛋白乙酰基转移酶4和从头DNA甲基转移酶相互作用，并且在转录激活后它与基因启动子中的DNA脱甲基化有关，共暗示参与基因调控而不是DNA修复。在这里，我们使用小鼠遗传学方法来确定这种多方面的DNA修复酶的生物学功能。我们发现，与其他DNA糖基化酶不同，TDG对于胚胎发育必不可少，并且该表型与影响发育基因表达的表观遗传畸变有关。 Tdg无效胚胎衍生的成纤维细胞（小鼠胚胎成纤维细胞，MEF）显示出受损的基因调节，与受影响的基因启动子处的组蛋白修饰和CpG甲基化不平衡。 TDG在成纤维细胞和胚胎干细胞（ESC）中均与此类基因的启动子相关，但表观遗传畸变仅在细胞谱系发生时出现。我们显示，TDG有助于整个细胞分化过程中维持活性和二价染色质的维持，促进染色质修饰复合物的正确组装并启动碱基切除修复以抵抗异常的Denovo甲基化。因此，我们得出的结论是，依赖TDG的DNA修复已发展为在谱系定型细胞中提供表观遗传稳定性。

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  • 来源
    《Nature》 |2011年第7334期|p.419-423|共5页
  • 作者

    Daniel Cortazar; Christophe Kunz; Jim Selfridge; Teresa Lettieri; Yusuke Saito; Eilidh MacDougall; Annika Wirz; David Schuermann; Angelika L. Jacobs; Fredy Siegrist; Roland Steinacher; Josef Jiricny; Adrian Bird; Primo Schar;

  • 作者单位

    Institute of Biochemistry and Genetics, Depa rtment of Biomedicine, University of Basel, 4048 Basel, Switzerland;

    rnInstitute of Biochemistry and Genetics, Depa rtment of Biomedicine, University of Basel, 4048 Basel, Switzerland;

    rnThe Wellcome Trust Centre for Celt Biology, University of Edinburgh, Edinburgh EH93JR, UK;

    rnInstitute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland;

    rnPharmaceutical Research, Global Preclinical Safety, F. Hoffmann-La Roche Ltd., 4058 Basel, Switzerland.;

    rnThe Wellcome Trust Centre for Celt Biology, University of Edinburgh, Edinburgh EH93JR, UK;

    rnInstitute of Biochemistry and Genetics, Depa rtment of Biomedicine, University of Basel, 4048 Basel, Switzerland;

    rnInstitute of Biochemistry and Genetics, Depa rtment of Biomedicine, University of Basel, 4048 Basel, Switzerland;

    rnInstitute of Biochemistry and Genetics, Depa rtment of Biomedicine, University of Basel, 4048 Basel, Switzerland;

    rnPharmaceutical Research, Global Preclinical Safety, F. Hoffmann-La Roche Ltd., 4058 Basel, Switzerland.;

    rnInstitute of Biochemistry and Genetics, Depa rtment of Biomedicine, University of Basel, 4048 Basel, Switzerland;

    rnInstitute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland;

    rnThe Wellcome Trust Centre for Celt Biology, University of Edinburgh, Edinburgh EH93JR, UK;

    rnInstitute of Biochemistry and Genetics, Depa rtment of Biomedicine, University of Basel, 4048 Basel, Switzerland;

  • 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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