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

Autor: Guangming Wu, Xiaofei Zhang, Xiwei Wang, He Liu, Yingying Lin, Siyuan Lin, Jie Wang, Junjie Shi, Jiekai Chen, Yu-Li Zhao, Mingwei Gao, Lei Chang, Xichen Bao, Duanqing Pei, Jiangping He, Kaixin Wu, Jiadong Liu, Guan-Zheng Luo, Man Zhang, Yaping Chen, Lingmei Jin
Rok vydání: 2021
Předmět:
Zdroj: Nature. 591:322-326
ISSN: 1476-4687
0028-0836
DOI: 10.1038/s41586-021-03313-9
Popis: 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. N6-methyladenosine RNA and its reader YTHDC1 serve as a bridge to silencing retrotransposons through the RNA derived from these retrotransposons in mouse ES cells.
Databáze: OpenAIRE
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