The RNA m 6 A reader YTHDC1 silences retrotransposons and guards ES cell identity

The RNA m 6 A reader YTHDC1 silences retrotransposons and guards ES cell identity

The RNA modification N -methyladenosine (m A) has critical roles in many biological processes . However, the function of m A in the early phase of mammalian development remains poorly understood. Here we show that the m A reader YT521-B homology-domain-containing protein 1 (YTHDC1) is required for t...

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Bibliographic Details
Published in:Nature (London) Vol. 591; no. 7849; p. 322
Main Authors: Liu, Jiadong, Gao, Mingwei, He, Jiangping, Wu, Kaixin, Lin, Siyuan, Jin, Lingmei, Chen, Yaping, Liu, He, Shi, Junjie, Wang, Xiwei, Chang, Lei, Lin, Yingying, Zhao, Yu-Li, Zhang, Xiaofei, Zhang, Man, Luo, Guan-Zheng, Wu, Guangming, Pei, Duanqing, Wang, Jie, Bao, Xichen, Chen, Jiekai
Format: Journal Article
Language:English
Published: England 01-03-2021
Subjects:
Adenosine - analogs & derivatives
Adenosine - metabolism
Animals
Chromatin - chemistry
Chromatin - genetics
Chromatin - metabolism
Gene Silencing
Histone-Lysine N-Methyltransferase - metabolism
Histones - chemistry
Histones - metabolism
Male
Mice
Mouse Embryonic Stem Cells - cytology
Mouse Embryonic Stem Cells - metabolism
Repressor Proteins - metabolism
Retroelements - genetics
RNA - chemistry
RNA - genetics
RNA - metabolism
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Summary:The RNA modification N -methyladenosine (m A) has critical roles in many biological processes . However, the function of m A in the early phase of mammalian development remains poorly understood. Here we show that the m A reader YT521-B homology-domain-containing protein 1 (YTHDC1) is required for the maintenance of mouse embryonic stem (ES) cells in an m A-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 m A 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 m A RNA and YTHDC1 in chromatin modification and retrotransposon repression.
ISSN:1476-4687