RNA Helicase DDX5 Inhibits Reprogramming to Pluripotency by miRNA-Based Repression of RYBP and its PRC1-Dependent and -Independent Functions

• Published in: Cell stem cell 2017-04, Vol.20 (4), p.462-477.e6
• Main Authors: Li, Huanhuan, Lai, Ping, Jia, Jinping, Song, Yawei, Xia, Qing, Huang, Kaimeng, He, Na, Ping, Wangfang, Chen, Jiayu, Yang, Zhongzhou, Li, Jiao, Yao, Mingze, Dong, Xiaotao, Zhao, Jicheng, Hou, Chunhui, Esteban, Miguel A., Gao, Shaorong, Pei, Duanqing, Hutchins, Andrew P., Yao, Hongjie
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions - genetics; Animals; Base Sequence; Cell Lineage - genetics; Cellular Reprogramming - genetics; DDX5; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Down-Regulation - genetics; F-Box Proteins - genetics; Fibroblasts - cytology; Fibroblasts - metabolism; Gene Expression Regulation, Developmental; Genetic Loci; H2AK119ub1; Histones - metabolism; Humans; Jumonji Domain-Containing Histone Demethylases - genetics; Mice; Mice, Inbred C57BL; microRNA-125b; MicroRNAs - genetics; MicroRNAs - metabolism; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; Octamer Transcription Factor-3 - metabolism; pluripotency; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; Polycomb Repressive Complex 1 - metabolism; polycomb repressor complex 1; Protein Binding; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA binding protein; RYBP; somatic cell reprogramming; Up-Regulation
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2016.12.002

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. [Display omitted] •DDX5 acts as a barrier to somatic cell reprogramming•DDX5 loss of function upregulates RYBP through microRNA-125b•Upregulated RYBP enhances H2AK119ub1 deposition at lineage-specific genes via PRC1•DDX5 silencing activates the OCT4-KDM2B network through RYBP independently of PRC1 RNA-binding proteins have poorly defined roles in somatic cell reprogramming. Li et al. show that the RNA-binding protein DDX5 erects an epigenetic barrier to reprogramming. DDX5 controls RYBP through microRNA-125b to suppress specific somatic genes through deposition of H2AK119ub1 while activating an OCT4-KDM2B pluripotent gene program.