Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for Xenopus eye and neural development.

IF 5.7 1区化学 Q2 CHEMISTRY, PHYSICAL

Journal of Chemical Theory and Computation Pub Date : 2012-12-07 DOI:10.1016/j.cell.2012.11.014

Yufei Xu, Chao Xu, Akiko Kato, Wolfram Tempel, Jose Garcia Abreu, Chuanbing Bian, Yeguang Hu, Di Hu, Bin Zhao, Tanja Cerovina, Jianbo Diao, Feizhen Wu, Housheng Hansen He, Qingyan Cui, Erin Clark, Chun Ma, Andrew Barbara, Gert Jan C Veenstra, Guoliang Xu, Ursula B Kaiser, X Shirley Liu, Stephen P Sugrue, Xi He, Jinrong Min, Yoichi Kato, Yujiang Geno Shi

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引用次数: 0

Abstract

Ten-Eleven Translocation (Tet) family of dioxygenases dynamically regulates DNA methylation and has been implicated in cell lineage differentiation and oncogenesis. Yet their functions and mechanisms of action in gene regulation and embryonic development are largely unknown. Here, we report that Xenopus Tet3 plays an essential role in early eye and neural development by directly regulating a set of key developmental genes. Tet3 is an active 5mC hydroxylase regulating the 5mC/5hmC status at target gene promoters. Biochemical and structural studies further demonstrate that the Tet3 CXXC domain is critical for specific Tet3 targeting. Finally, we show that the enzymatic activity and CXXC domain are both crucial for Tet3's biological function. Together, these findings define Tet3 as a transcription regulator and reveal a molecular mechanism by which the 5mC hydroxylase and DNA binding activities of Tet3 cooperate to control target gene expression and embryonic development.

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Tet3 CXXC结构域和二氧酶活性协同调控章鱼眼睛和神经发育的关键基因。

十-十一转位（Tet）二氧酶家族动态调节 DNA 甲基化，并与细胞系分化和肿瘤发生有关。然而，它们在基因调控和胚胎发育中的功能和作用机制在很大程度上还不为人知。在这里，我们报告了爪蟾 Tet3 通过直接调控一系列关键发育基因，在早期眼睛和神经发育中发挥着重要作用。Tet3 是一种活性 5mC 羟化酶，可调节目标基因启动子的 5mC/5hmC 状态。生化和结构研究进一步证明，Tet3 的 CXXC 结构域对特异性 Tet3 靶向至关重要。最后，我们证明酶活性和 CXXC 结构域对 Tet3 的生物功能都至关重要。这些发现共同确定了 Tet3 是一种转录调节因子，并揭示了 Tet3 的 5mC 羟化酶和 DNA 结合活性合作控制目的基因表达和胚胎发育的分子机制。

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来源期刊

Journal of Chemical Theory and Computation 化学-物理：原子、分子和化学物理

CiteScore

9.90

自引率

16.40%

发文量

568

审稿时长

1 months

期刊介绍： The Journal of Chemical Theory and Computation invites new and original contributions with the understanding that, if accepted, they will not be published elsewhere. Papers reporting new theories, methodology, and/or important applications in quantum electronic structure, molecular dynamics, and statistical mechanics are appropriate for submission to this Journal. Specific topics include advances in or applications of ab initio quantum mechanics, density functional theory, design and properties of new materials, surface science, Monte Carlo simulations, solvation models, QM/MM calculations, biomolecular structure prediction, and molecular dynamics in the broadest sense including gas-phase dynamics, ab initio dynamics, biomolecular dynamics, and protein folding. The Journal does not consider papers that are straightforward applications of known methods including DFT and molecular dynamics. The Journal favors submissions that include advances in theory or methodology with applications to compelling problems.