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METTL3 regulates heterochromatin in mouse embryonic stem cells

Author

Listed:
  • Wenqi Xu

    (Fudan University
    Fudan University
    Fudan University)

  • Jiahui Li

    (Fudan University
    Fudan University)

  • Chenxi He

    (Fudan University
    Fudan University)

  • Jing Wen

    (Fudan University
    Fudan University)

  • Honghui Ma

    (Fudan University
    Fudan University)

  • Bowen Rong

    (Fudan University
    Fudan University)

  • Jianbo Diao

    (Fudan University
    Fudan University)

  • Liyong Wang

    (Fudan University
    Fudan University)

  • Jiahua Wang

    (Fudan University
    Fudan University)

  • Feizhen Wu

    (Fudan University
    Fudan University)

  • Li Tan

    (Fudan University
    Fudan University)

  • Yujiang Geno Shi

    (Harvard Medical School)

  • Yang Shi

    (University of Oxford)

  • Hongjie Shen

    (Fudan University
    Fudan University)

Abstract

METTL3 (methyltransferase-like 3) mediates the N6-methyladenosine (m6A) methylation of mRNA, which affects the stability of mRNA and its translation into protein1. METTL3 also binds chromatin2–4, but the role of METTL3 and m6A methylation in chromatin is not fully understood. Here we show that METTL3 regulates mouse embryonic stem-cell heterochromatin, the integrity of which is critical for silencing retroviral elements and for mammalian development5. METTL3 predominantly localizes to the intracisternal A particle (IAP)-type family of endogenous retroviruses. Knockout of Mettl3 impairs the deposition of multiple heterochromatin marks onto METTL3-targeted IAPs, and upregulates IAP transcription, suggesting that METTL3 is important for the integrity of IAP heterochromatin. We provide further evidence that RNA transcripts derived from METTL3-bound IAPs are associated with chromatin and are m6A-methylated. These m6A-marked transcripts are bound by the m6A reader YTHDC1, which interacts with METTL3 and in turn promotes the association of METTL3 with chromatin. METTL3 also interacts physically with the histone 3 lysine 9 (H3K9) tri-methyltransferase SETDB1 and its cofactor TRIM28, and is important for their localization to IAPs. Our findings demonstrate that METTL3-catalysed m6A modification of RNA is important for the integrity of IAP heterochromatin in mouse embryonic stem cells, revealing a mechanism of heterochromatin regulation in mammals.

Suggested Citation

  • Wenqi Xu & Jiahui Li & Chenxi He & Jing Wen & Honghui Ma & Bowen Rong & Jianbo Diao & Liyong Wang & Jiahua Wang & Feizhen Wu & Li Tan & Yujiang Geno Shi & Yang Shi & Hongjie Shen, 2021. "METTL3 regulates heterochromatin in mouse embryonic stem cells," Nature, Nature, vol. 591(7849), pages 317-321, March.
    • Handle: RePEc:nat:nature:v:591:y:2021:i:7849:d:10.1038_s41586-021-03210-1
    DOI: 10.1038/s41586-021-03210-1
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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. 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.
    3. Xin Yang & Robinson Triboulet & Qi Liu & Erdem Sendinc & Richard I. Gregory, 2022. "Exon junction complex shapes the m6A epitranscriptome," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. 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.
    5. Chang Liu & Xiaoyang Dou & Yutao Zhao & Linda Zhang & Lisheng Zhang & Qing Dai & Jun Liu & Tong Wu & Yu Xiao & Chuan He, 2024. "IGF2BP3 promotes mRNA degradation through internal m7G modification," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    6. Xinzhi Li & Bingchuan Yuan & Min Lu & Yuqin Wang & Na Ding & Chunhong Liu & Ming Gao & Zhicheng Yao & Shiyan Zhang & Yujun Zhao & Liwei Xie & Zheng Chen, 2021. "The methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    7. 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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