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

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, Guan-Zheng Luo, Guangming Wu, Duanqing Pei, Jie Wang, Xichen Bao and Jiekai Chen ()
Additional contact information
Jiadong Liu: Chinese Academy of Sciences
Mingwei Gao: Chinese Academy of Sciences
Jiangping He: Guangzhou Regenerative Medicine and Health GuangDong Laboratory
Kaixin Wu: Chinese Academy of Sciences
Siyuan Lin: Chinese Academy of Sciences
Lingmei Jin: Chinese Academy of Sciences
Yaping Chen: Chinese Academy of Sciences
He Liu: Guangzhou Regenerative Medicine and Health GuangDong Laboratory
Junjie Shi: 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
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
Jie Wang: Chinese Academy of Sciences
Xichen Bao: Chinese Academy of Sciences
Jiekai Chen: Chinese Academy of Sciences

Nature, 2021, vol. 591, issue 7849, 322-326

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03313-9

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