title: RNA Helicase DDX5 Inhibits Reprogramming to Pluripotency by miRNA-Based Repression of RYBP and its PRC1-Dependent and -Independent Functions.
abstract: RNA-binding proteins (RBPs), in addition to their functions in cellular homeostasis, play important roles in lineage specification and maintaining cellular identity. Despite their diverse and essential functions, which touch on nearly all aspects of RNA metabolism, the roles of RBPs in somatic cell reprogramming are poorly understood. Here we show that the DEAD-box RBP DDX5 inhibits reprogramming by repressing the expression and function of the non-canonical polycomb complex 1 (PRC1) subunit RYBP. Disrupting Ddx5 expression improves the efficiency of iPSC generation and impedes processing of miR-125b, leading to Rybp upregulation and suppression of lineage-specific genes via RYBP-dependent ubiquitination of H2AK119. Furthermore, RYBP is required for PRC1-independent recruitment of OCT4 to the promoter of Kdm2b, a histone demethylase gene that promotes reprogramming by reactivating endogenous pluripotency genes. Together, these results reveal important functions of DDX5 in regulating reprogramming and highlight the importance of a Ddx5-miR125b-Rybp axis in controlling cell fate.
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Center for Excellence in Molecular Cell Science, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; GZMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou 511436, China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Center for Excellence in Molecular Cell Science, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Lai
authors.affiliation: Laboratory of Translational Genomics, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Jinping
authors.initials: J
authors.lastname: Jia
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Center for Excellence in Molecular Cell Science, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Song
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Center for Excellence in Molecular Cell Science, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xia
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Center for Excellence in Molecular Cell Science, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Kaimeng
authors.initials: K
authors.lastname: Huang
authors.affiliation: Department of Biology, Southern University of Science and Technology of China, Shenzhen 518055, China.
authors.forename: Na
authors.initials: N
authors.lastname: He
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Center for Excellence in Molecular Cell Science, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Wangfang
authors.initials: W
authors.lastname: Ping
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Chen
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Center for Excellence in Molecular Cell Science, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Zhongzhou
authors.initials: Z
authors.lastname: Yang
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Center for Excellence in Molecular Cell Science, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Center for Excellence in Molecular Cell Science, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Mingze
authors.initials: M
authors.lastname: Yao
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Center for Excellence in Molecular Cell Science, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Dong
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jicheng
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Biology, Southern University of Science and Technology of China, Shenzhen 518055, China.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Hou
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Center for Excellence in Molecular Cell Science, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Esteban
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Shaorong
authors.initials: S
authors.lastname: Gao
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Center for Excellence in Molecular Cell Science, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Duanqing
authors.initials: D
authors.lastname: Pei
authors.affiliation: Department of Biology, Southern University of Science and Technology of China, Shenzhen 518055, China.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Hutchins
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Center for Excellence in Molecular Cell Science, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China. Electronic address: yao_hongjie@gibh.ac.cn.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Yao
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D019070:Cell Lineage / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics*; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D044783:F-Box Proteins / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D056426:Genetic Loci; D006657:Histones / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; D044783:F-Box Proteins; D006657:Histones; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D012097:Repressor Proteins; C120616:Rybp protein, mouse; D056484:Jumonji Domain-Containing Histone Demethylases; C524747:Kdm2b protein, mouse; D063150:Polycomb Repressive Complex 1; C506751:Ddx5 protein, mouse; D053487:DEAD-box RNA Helicases
keywords: DDX5; H2AK119ub1; RNA binding protein; RYBP; microRNA-125b; pluripotency; polycomb repressor complex 1; somatic cell reprogramming