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

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; Yuan Li; Yasong Wu; Andrew P Hutchins; Dongye Wang; Hung-Fat Tse; Axel Schambach; Jonathan Frampton; Baoming Qin; Xichen Bao; Hongjie Yao; Biliang Zhang; Hao Sun; Duanqing Pei; Huating Wang; Jun Wang; Miguel A Esteban

doi:10.1016/j.stem.2014.09.018

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

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, Yuan Li, Yasong Wu, Andrew P Hutchins, Dongye WangHung-Fat Tse, Axel Schambach, Jonathan Frampton, Baoming Qin, Xichen Bao, Hongjie Yao, Biliang Zhang, Hao Sun, Duanqing Pei, Huating Wang, Jun Wang, Miguel A Esteban

Research output: Contribution to journal › Article › peer-review

43 Citations (Scopus)

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.

Original language	English
Pages (from-to)	574-88
Number of pages	15
Journal	Cell stem cell
Volume	15
Issue number	5
DOIs	https://doi.org/10.1016/j.stem.2014.09.018
Publication status	Published - 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

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10.1016/j.stem.2014.09.018

Developing Stem Cell Therapies for the Treatment of Inherited and Acquired Liver Disease
Frampton, J. & Newsome, P.
Medical Research Council
3/12/12 → 30/09/13
Project: Research Councils

Cite this

@article{d49e3041e6c6469ab34472313e35a44c,

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.",

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",

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

year = "2014",

month = nov,

day = "6",

doi = "10.1016/j.stem.2014.09.018",

language = "English",

volume = "15",

pages = "574--88",

journal = "Cell stem cell",

issn = "1934-5909",

publisher = "Elsevier",

number = "5",

}

Liu, L, Xu, Y, He, M, Zhang, M, Cui, F, Lu, L, Yao, M, Tian, W, Benda, C, Zhuang, Q, Huang, Z, Li, W, Li, X, Zhao, P, Fan, W, Luo, Z, Li, Y, Wu, Y, Hutchins, AP, Wang, D, Tse, H-F, Schambach, A, Frampton, J, Qin, B, Bao, X, Yao, H, Zhang, B, Sun, H, Pei, D, Wang, H, Wang, J & Esteban, MA 2014, 'Transcriptional pause release is a rate-limiting step for somatic cell reprogramming', Cell stem cell, vol. 15, no. 5, pp. 574-88. https://doi.org/10.1016/j.stem.2014.09.018

TY - JOUR

T1 - Transcriptional pause release is a rate-limiting step for somatic cell reprogramming

AU - Liu, Longqi

AU - Xu, Yan

AU - He, Minghui

AU - Zhang, Meng

AU - Cui, Fenggong

AU - Lu, Leina

AU - Yao, Mingze

AU - Tian, Weihua

AU - Benda, Christina

AU - Zhuang, Qiang

AU - Huang, Zhijian

AU - Li, Wenjuan

AU - Li, Xiangchun

AU - Zhao, Ping

AU - Fan, Wenxia

AU - Luo, Zhiwei

AU - Li, Yuan

AU - Wu, Yasong

AU - Hutchins, Andrew P

AU - Wang, Dongye

AU - Tse, Hung-Fat

AU - Schambach, Axel

AU - Frampton, Jonathan

AU - Qin, Baoming

AU - Bao, Xichen

AU - Yao, Hongjie

AU - Zhang, Biliang

AU - Sun, Hao

AU - Pei, Duanqing

AU - Wang, Huating

AU - Wang, Jun

AU - Esteban, Miguel A

PY - 2014/11/6

Y1 - 2014/11/6

N2 - 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.

AB - 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.

KW - Animals

KW - Base Sequence

KW - Cellular Reprogramming

KW - Cyclin-Dependent Kinase 9

KW - Embryo, Mammalian

KW - Embryonic Stem Cells

KW - Fibroblasts

KW - Gene Expression Regulation

KW - Genome

KW - HEK293 Cells

KW - Humans

KW - Kinetics

KW - Kruppel-Like Transcription Factors

KW - Mice

KW - Molecular Sequence Data

KW - Nuclear Proteins

KW - Pluripotent Stem Cells

KW - Positive Transcriptional Elongation Factor B

KW - Promoter Regions, Genetic

KW - Protein Binding

KW - RNA Polymerase II

KW - Transcription Factors

KW - Transcription, Genetic

U2 - 10.1016/j.stem.2014.09.018

DO - 10.1016/j.stem.2014.09.018

M3 - Article

C2 - 25312495

SN - 1934-5909

VL - 15

SP - 574

EP - 588

JO - Cell stem cell

JF - Cell stem cell

IS - 5

ER -

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

Abstract

Keywords

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Projects

Developing Stem Cell Therapies for the Treatment of Inherited and Acquired Liver Disease

Cite this