Wenqiang Liu
Jiayin Guo
Yuanyuan Liu
Xuelian Liu
Jun Liu
Xiaoyang Dou
Rongrong Le
Yixin Huang
Chong Li
Lingyue Yang
Xiaochen Kou
Yanhong Zhao
You Wu
Jiayu Chen
Hong Wang
Bin Shen
Yawei Gao
Shaorong Gao
1 Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China;
2 Clinical and Translation Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China;
3 State Key Laboratory of Reproductive Medicine, Department of Prenatal Diagnosis, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing 211166, China;
4 School of Life Sciences, Peking University, Beijing 100871, China;
5 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China;
6 Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA;
7 Howard Hughes Medical Institute, Chicago, IL 60637, USA
Received Date: 2021-03-03
Rev Recd Date:2021-03-18
Abstract
Abstract
N6-methyladenosine (m6A) on chromosome-associated regulatory RNAs (carRNAs), including repeat RNAs, plays important roles in tuning the chromatin state and transcription, but the intrinsic mechanism remains unclear. Here, we report that YTHDC1 plays indispensable roles in the self-renewal and differentiation potency of mouse embryonic stem cells (ESCs), which highly depends on the m6A-binding ability. Ythdc1 is required for sufficient rRNA synthesis and repression of the 2-cell (2C) transcriptional program in ESCs, which recapitulates the transcriptome regulation by the LINE1 scaffold. Detailed analyses revealed that YTHDC1 recognizes m6A on LINE1 RNAs in the nucleus and regulates the formation of the LINE1-NCL partnership and the chromatin recruitment of KAP1. Moreover, the establishment of H3K9me3 on 2C-related retrotransposons is interrupted in Ythdc1-depleted ESCs and inner cell mass (ICM) cells, which consequently increases the transcriptional activities. Our study reveals a role of m6A in regulating the RNA scaffold, providing a new model for the RNA-chromatin cross-talk.Keywords: YTHDC1,
LINE1-scaffold complex,
2-cell,
retrotransposons,
H3K9me3
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