title: Transcriptional pause release is a rate-limiting step for somatic cell reprogramming.
abstract: Reactivation of the pluripotency network during somatic cell reprogramming by exogenous transcription factors involves chromatin remodeling and the recruitment of RNA polymerase II (Pol II) to target loci. Here, we report that Pol II is engaged at pluripotency promoters in reprogramming but remains paused and inefficiently released. We also show that bromodomain-containing protein 4 (BRD4) stimulates productive transcriptional elongation of pluripotency genes by dissociating the pause release factor P-TEFb from an inactive complex containing HEXIM1. Consequently, BRD4 overexpression enhances reprogramming efficiency and HEXIM1 suppresses it, whereas Brd4 and Hexim1 knockdown do the opposite. We further demonstrate that the reprogramming factor KLF4 helps recruit P-TEFb to pluripotency promoters. Our work thus provides a mechanism for explaining the reactivation of pluripotency genes in reprogramming and unveils an unanticipated role for KLF4 in transcriptional pause release.
authors.affiliation: Laboratory of Chromatin and Human Disease, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Longqi
authors.initials: L
authors.lastname: Liu
authors.affiliation: Laboratory of Chromatin and Human Disease, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: xu_yan@gibh.ac.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Minghui
authors.initials: M
authors.lastname: He
authors.affiliation: Laboratory of Chromatin and Human Disease, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; School of Life Sciences, Anhui University, Hefei 230601, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Laboratory of Chromatin and Human Disease, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China.
authors.forename: Fenggong
authors.initials: F
authors.lastname: Cui
authors.affiliation: Li Ka Shing Institute of Health Sciences, Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Leina
authors.initials: L
authors.lastname: Lu
authors.affiliation: Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China.
authors.forename: Mingze
authors.initials: M
authors.lastname: Yao
authors.affiliation: Laboratory of Chromatin and Human Disease, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Tian
authors.affiliation: Laboratory of Chromatin and Human Disease, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Christina
authors.initials: C
authors.lastname: Benda
authors.affiliation: Laboratory of Chromatin and Human Disease, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhuang
authors.affiliation: Laboratory of Chromatin and Human Disease, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Laboratory of Chromatin and Human Disease, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Li
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Xiangchun
authors.initials: X
authors.lastname: Li
authors.affiliation: Laboratory of Chromatin and Human Disease, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Laboratory of Chromatin and Human Disease, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China.
authors.forename: Wenxia
authors.initials: W
authors.lastname: Fan
authors.affiliation: Laboratory of Chromatin and Human Disease, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Yasong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Hutchins
authors.affiliation: Laboratory of Chromatin and Human Disease, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Drug Discovery Pipeline Group, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China.
authors.forename: Dongye
authors.initials: D
authors.lastname: Wang
authors.affiliation: Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong SAR, China; Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, the University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, China; Shenzhen Institutes of Research and Innovation, the University of Hong Kong, Hong Kong SAR, China.
authors.forename: Hung-Fat
authors.initials: HF
authors.lastname: Tse
authors.affiliation: Department of Experimental Hematology, Hannover Medical School, Hannover D-30625, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Schambach
authors.affiliation: Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Jon
authors.initials: J
authors.lastname: Frampton
authors.affiliation: Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, the University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, China.
authors.forename: Baoming
authors.initials: B
authors.lastname: Qin
authors.affiliation: Laboratory of Chromatin and Human Disease, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China.
authors.forename: Xichen
authors.initials: X
authors.lastname: Bao
authors.affiliation: Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Yao
authors.affiliation: Laboratory of RNA Chemical Biology, State Key Laboratory of Respiratory Diseases of the Chinese Academy of Sciences, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China.
authors.forename: Biliang
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Li Ka Shing Institute of Health Sciences, Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Sun
authors.affiliation: Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, the University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, China.
authors.forename: Duanqing
authors.initials: D
authors.lastname: Pei
authors.affiliation: Li Ka Shing Institute of Health Sciences, Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Huating
authors.initials: H
authors.lastname: Wang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Laboratory of Chromatin and Human Disease, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China; Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, the University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, China. Electronic address: miguel@gibh.ac.cn.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Esteban
mesh_terms: D000818:Animals; D001483:Base Sequence; D065150:Cellular Reprogramming / Q000235:genetics*; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D016678:Genome; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D012319:RNA Polymerase II / Q000378:metabolism; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000092468:Bromodomain Containing Proteins
chemical_list: D042863:Cyclin-Dependent Kinase 9; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D042925:Positive Transcriptional Elongation Factor B; D012319:RNA Polymerase II; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C118642:Hexim1 protein, mouse; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; C467972:Cdk9 protein, mouse