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The RNA m6A reader YTHDC1 silences retrotransposons and guards ES cell identity

Author

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  • Jiadong Liu

    (Chinese Academy of Sciences
    Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine
    University of Chinese Academy of Sciences)

  • Mingwei Gao

    (Chinese Academy of Sciences
    Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine
    University of Chinese Academy of Sciences)

  • Jiangping He

    (Guangzhou Regenerative Medicine and Health GuangDong Laboratory)

  • Kaixin Wu

    (Chinese Academy of Sciences
    The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital
    Southern Medical University)

  • Siyuan Lin

    (Chinese Academy of Sciences
    Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine)

  • Lingmei Jin

    (Chinese Academy of Sciences
    Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine
    University of Chinese Academy of Sciences)

  • Yaping Chen

    (Chinese Academy of Sciences
    Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine
    University of Chinese Academy of Sciences)

  • He Liu

    (Guangzhou Regenerative Medicine and Health GuangDong Laboratory
    Guangzhou Medical University)

  • Junjie Shi

    (Chinese Academy of Sciences
    Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine
    University of Chinese Academy of Sciences)

  • Xiwei Wang

    (Guangzhou Regenerative Medicine and Health GuangDong Laboratory)

  • Lei Chang

    (Guangzhou Regenerative Medicine and Health GuangDong Laboratory)

  • Yingying Lin

    (Sun Yat-Sen University)

  • Yu-Li Zhao

    (Sun Yat-Sen University)

  • Xiaofei Zhang

    (Chinese Academy of Sciences
    Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine
    Guangzhou Regenerative Medicine and Health GuangDong Laboratory)

  • Man Zhang

    (Guangzhou Regenerative Medicine and Health GuangDong Laboratory)

  • Guan-Zheng Luo

    (Sun Yat-Sen University)

  • Guangming Wu

    (Guangzhou Regenerative Medicine and Health GuangDong Laboratory)

  • Duanqing Pei

    (Chinese Academy of Sciences
    Guangzhou Regenerative Medicine and Health GuangDong Laboratory
    Westlake University)

  • Jie Wang

    (Chinese Academy of Sciences
    Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine)

  • Xichen Bao

    (Chinese Academy of Sciences
    Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine
    Guangzhou Regenerative Medicine and Health GuangDong Laboratory)

  • Jiekai Chen

    (Chinese Academy of Sciences
    Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine
    University of Chinese Academy of Sciences
    Guangzhou Regenerative Medicine and Health GuangDong Laboratory)

Abstract

The RNA modification N6-methyladenosine (m6A) has critical roles in many biological processes1,2. However, the function of m6A in the early phase of mammalian development remains poorly understood. Here we show that the m6A reader YT521-B homology-domain-containing protein 1 (YTHDC1) is required for the maintenance of mouse embryonic stem (ES) cells in an m6A-dependent manner, and that its deletion initiates cellular reprogramming to a 2C-like state. Mechanistically, YTHDC1 binds to the transcripts of retrotransposons (such as intracisternal A particles, ERVK and LINE1) in mouse ES cells and its depletion results in the reactivation of these silenced retrotransposons, accompanied by a global decrease in SETDB1-mediated trimethylation at lysine 9 of histone H3 (H3K9me3). We further demonstrate that YTHDC1 and its target m6A RNAs act upstream of SETDB1 to repress retrotransposons and Dux, the master inducer of the two-cell stage (2C)-like program. This study reveals an essential role for m6A RNA and YTHDC1 in chromatin modification and retrotransposon repression.

Suggested Citation

  • Jiadong Liu & Mingwei Gao & Jiangping He & Kaixin Wu & Siyuan Lin & Lingmei Jin & Yaping Chen & He Liu & Junjie Shi & Xiwei Wang & Lei Chang & Yingying Lin & Yu-Li Zhao & Xiaofei Zhang & Man Zhang & G, 2021. "The RNA m6A reader YTHDC1 silences retrotransposons and guards ES cell identity," Nature, Nature, vol. 591(7849), pages 322-326, March.
    • Handle: RePEc:nat:nature:v:591:y:2021:i:7849:d:10.1038_s41586-021-03313-9
    DOI: 10.1038/s41586-021-03313-9
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    Citations

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    Cited by:

    1. Yanan Liu & Longmiao Hu & Zhengzhen Wu & Kun Yuan & Guangliang Hong & Zhengke Lian & Juanjuan Feng & Na Li & Dali Li & Jiemin Wong & Jiekai Chen & Mingyao Liu & Jiangping He & Xiufeng Pang, 2023. "Loss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Zhen-Dong Zhong & Ying-Yuan Xie & Hong-Xuan Chen & Ye-Lin Lan & Xue-Hong Liu & Jing-Yun Ji & Fu Wu & Lingmei Jin & Jiekai Chen & Daniel W. Mak & Zhang Zhang & Guan-Zheng Luo, 2023. "Systematic comparison of tools used for m6A mapping from nanopore direct RNA sequencing," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Dasol Han & Guojing Liu & Yujeong Oh & Seyoun Oh & Seungbok Yang & Lori Mandjikian & Neha Rani & Maria C. Almeida & Kenneth S. Kosik & Jiwon Jang, 2023. "ZBTB12 is a molecular barrier to dedifferentiation in human pluripotent stem cells," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Chunhong Yu & Xiaoyun Lei & Fang Chen & Song Mao & Lu Lv & Honglu Liu & Xueying Hu & Runhan Wang & Licong Shen & Na Zhang & Yang Meng & Yunfan Shen & Jiale Chen & Pishun Li & Shi Huang & Changwei Lin , 2022. "ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Huan Yao & Chun-Chun Gao & Danru Zhang & Jiawei Xu & Gege Song & Xiu Fan & Dao-Bo Liang & Yu-Sheng Chen & Qian Li & Yanjie Guo & Yu-Ting Cai & Lulu Hu & Yong-Liang Zhao & Ying-Pu Sun & Ying Yang & Jia, 2023. "scm6A-seq reveals single-cell landscapes of the dynamic m6A during oocyte maturation and early embryonic development," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. Yan Xu & Zhuowei Zhou & Xinmei Kang & Lijie Pan & Chang Liu & Xiaoqi Liang & Jiajie Chu & Shuai Dong & Yanli Li & Qiuli Liu & Yuetong Sun & Shanshan Yu & Qi Zhang, 2022. "Mettl3-mediated mRNA m6A modification controls postnatal liver development by modulating the transcription factor Hnf4a," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    7. Zhengyi Li & Haiyan Xu & Jiaqun Li & Xiao Xu & Junjiao Wang & Danya Wu & Jiateng Zhang & Juan Liu & Ziwei Xue & Guankai Zhan & Bobby Cheng Peow Tan & Di Chen & Yun-Shen Chan & Huck Hui Ng & Wanlu Liu , 2023. "Selective binding of retrotransposons by ZFP352 facilitates the timely dissolution of totipotency network," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    8. Yongli Shan & Yanqi Zhang & Yanxing Wei & Cong Zhang & Huaisong Lin & Jiangping He & Junwei Wang & Wenjing Guo & Heying Li & Qianyu Chen & Tiancheng Zhou & Qi Xing & Yancai Liu & Jiekai Chen & Guangji, 2024. "METTL3/METTL14 maintain human nucleoli integrity by mediating SUV39H1/H2 degradation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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