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

Cell. 2012 Dec 7;151(6):1200-13. doi: 10.1016/j.cell.2012.11.014.

Yufei Xu ¹, 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

Affiliations

Affiliation

1 Division of Endocrinology, Diabetes and Hypertension, Departments of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

PMID: 23217707 DOI: 10.1016/j.cell.2012.11.014

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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