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

Research output: Contribution to journalArticle

Authors

  • Longqi Liu
  • Yan Xu
  • Minghui He
  • Meng Zhang
  • Fenggong Cui
  • Leina Lu
  • Mingze Yao
  • Weihua Tian
  • Christina Benda
  • Qiang Zhuang
  • Zhijian Huang
  • Wenjuan Li
  • Xiangchun Li
  • Ping Zhao
  • Wenxia Fan
  • Zhiwei Luo
  • Yasong Wu
  • Andrew P Hutchins
  • Dongye Wang
  • Hung-Fat Tse
  • Axel Schambach
  • Baoming Qin
  • Xichen Bao
  • Hongjie Yao
  • Biliang Zhang
  • Hao Sun
  • Duanqing Pei
  • Huating Wang
  • Jun Wang
  • Miguel A Esteban

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.

Details

Original languageEnglish
Pages (from-to)574-88
Number of pages15
JournalCell stem cell
Volume15
Issue number5
Publication statusPublished - 6 Nov 2014

Keywords

  • Animals, Base Sequence, Cellular Reprogramming, Cyclin-Dependent Kinase 9, Embryo, Mammalian, Embryonic Stem Cells, Fibroblasts, Gene Expression Regulation, Genome, HEK293 Cells, Humans, Kinetics, Kruppel-Like Transcription Factors, Mice, Molecular Sequence Data, Nuclear Proteins, Pluripotent Stem Cells, Positive Transcriptional Elongation Factor B, Promoter Regions, Genetic, Protein Binding, RNA Polymerase II, Transcription Factors, Transcription, Genetic