Transcriptional pause release is a rate-limiting step for somatic cell reprogramming

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...

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Podrobná bibliografia
Vydané v:	Cell stem cell Ročník 15; číslo 5; s. 574
Hlavní autori:	Liu, Longqi, Xu, Yan, He, Minghui, Zhang, Meng, Cui, Fenggong, Lu, Leina, Yao, Mingze, Tian, Weihua, Benda, Christina, Zhuang, Qiang, Huang, Zhijian, Li, Wenjuan, Li, Xiangchun, Zhao, Ping, Fan, Wenxia, Luo, Zhiwei, Li, Yuan, Wu, Yasong, Hutchins, Andrew P, Wang, Dongye, Tse, Hung-Fat, Schambach, Axel, Frampton, Jon, Qin, Baoming, Bao, Xichen, Yao, Hongjie, Zhang, Biliang, Sun, Hao, Pei, Duanqing, Wang, Huating, Wang, Jun, Esteban, Miguel A
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 06.11.2014
Predmet:	Animals Base Sequence Cellular Reprogramming - genetics Cyclin-Dependent Kinase 9 - metabolism Embryo, Mammalian - cytology Embryonic Stem Cells - cytology Embryonic Stem Cells - metabolism Fibroblasts - cytology Fibroblasts - metabolism Gene Expression Regulation Genome HEK293 Cells Humans Kinetics Kruppel-Like Factor 4 Kruppel-Like Transcription Factors - metabolism Mice Molecular Sequence Data Nuclear Proteins - metabolism Pluripotent Stem Cells - cytology Pluripotent Stem Cells - metabolism Positive Transcriptional Elongation Factor B - metabolism Promoter Regions, Genetic Protein Binding - genetics RNA Polymerase II - metabolism RNA-Binding Proteins Transcription Factors - metabolism Transcription, Genetic
ISSN:	1875-9777, 1875-9777
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Popis
Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1875-9777 1875-9777
DOI:	10.1016/j.stem.2014.09.018