Nuclear m^(6)A reader YTHDC1 regulates the scaffold function of LINE1 RNA in mouse ESCs and early embryos  

作　　者：Chuan Chen 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 

机构地区：[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

出　　处：《Protein & Cell》2021年第6期455-474,共20页蛋白质与细胞（英文版）

基　　金：This work was supported by the National Key R&D Program of China(2016YFA0100400,2020YFA0113200,2018YFA0108900 and 2016YFC1000600);the National Natural Science Foundation of China(31922022,31771646,82022027,31721003,31970796,31871448 and 31871446);the Shanghai Rising-Star Program(19QA1409600);the Shanghai Municipal Medical and Health Discipline Construction Projects(2017ZZ02015);the Fundamental Research Funds for the Central Universities(1515219049 and 22120200410);the Major Program of the Development Fund for Shanghai Zhangjiang National Innovation Demonstration Zone(ZJ2018-ZD-004).

摘　　要：N^(6)-methyladenosine(m^(6)A)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 m^(6)A-binding ability.Ythdcl 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 m^(6)A 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 retrotrans-posons is interrupted in Ythdcl-depleted ESCs and inner cell mass(ICM)cells,which consequently increases the transcriptional activities.Our study reveals a role of m^(6)A in regulating the RNA scaffold,providing a new model for the RNA-chromatin cross-talk.

关 键 词：YTHDC1 LINE1-scaffold complex 2-cell RETROTRANSPOSONS H3K9me3 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]