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Mol Cell. 2018 Mar 15;69(6):1028-1038.e6. doi: 10.1016/j.molcel.2018.02.015.

Zc3h13 Regulates Nuclear RNA m6A Methylation and Mouse Embryonic Stem Cell Self-Renewal.

Author information

1
Institute of Clinical Science, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.
2
Department of Systems Biology, Institutes of Biomedical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
3
Institute of Clinical Science, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China; Key Laboratory of Birth Defect, Children's Hospital of Fudan University, Shanghai 201102, China.
4
Institute of Clinical Science, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China; Key Laboratory of Birth Defect, Children's Hospital of Fudan University, Shanghai 201102, China; Division of Endocrinology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: yujiang_shi@hms.harvard.edu.
5
Department of Chemistry, and Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA; Howard Hughes Medical Institute, University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA. Electronic address: chuanhe@uchicago.edu.
6
Institute of Clinical Science, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China; Key Laboratory of Birth Defect, Children's Hospital of Fudan University, Shanghai 201102, China; Newborn Medicine Division, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: yshi@hms.harvard.edu.
7
Institute of Clinical Science, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China; Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Key Laboratory of Epigenetics, Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China. Electronic address: diao2010@gmail.com.

Abstract

N6-methyladenosine (m6A) is an abundant modification in eukaryotic mRNA, regulating mRNA dynamics by influencing mRNA stability, splicing, export, and translation. However, the precise m6A regulating machinery still remains incompletely understood. Here we demonstrate that ZC3H13, a zinc-finger protein, plays an important role in modulating RNA m6A methylation in the nucleus. We show that knockdown of Zc3h13 in mouse embryonic stem cell significantly decreases global m6A level on mRNA. Upon Zc3h13 knockdown, a great majority of WTAP, Virilizer, and Hakai translocate to the cytoplasm, suggesting that Zc3h13 is required for nuclear localization of the Zc3h13-WTAP-Virilizer-Hakai complex, which is important for RNA m6A methylation. Finally, Zc3h13 depletion, as does WTAP, Virilizer, or Hakai, impairs self-renewal and triggers mESC differentiation. Taken together, our findings demonstrate that Zc3h13 plays a critical role in anchoring WTAP, Virilizer, and Hakai in the nucleus to facilitate m6A methylation and to regulate mESC self-renewal.

KEYWORDS:

Zc3h13; m(6)A; mESC self-renewal; nuclear localization

PMID:
29547716
PMCID:
PMC5858226
DOI:
10.1016/j.molcel.2018.02.015
[Indexed for MEDLINE]
Free PMC Article

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