Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation

Ka Lung Cheung; Fan Zhang; Anbalagan Jaganathan; Rajal Sharma; Qiang Zhang; Tsuyoshi Konuma; Tong Shen; June Yong Lee; Chunyan Ren; Chih Hung Chen; Geming Lu; Matthew R. Olson; Weijia Zhang; Mark H. Kaplan; Dan R. Littman; Martin J. Walsh; Huabao Xiong; Lei Zeng; Ming Ming Zhou

doi:10.1016/j.molcel.2016.12.022

Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation

Ka Lung Cheung, Fan Zhang, Anbalagan Jaganathan, Rajal Sharma, Qiang Zhang, Tsuyoshi Konuma, Tong Shen, June Yong Lee, Chunyan Ren, Chih Hung Chen, Geming Lu, Matthew R. Olson, Weijia Zhang, Mark H. Kaplan, Dan R. Littman, Martin J. Walsh, Huabao Xiong, Lei Zeng, Ming Ming Zhou

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106 Scopus citations

Abstract

The BET proteins are major transcriptional regulators and have emerged as new drug targets, but their functional distinction has remained elusive. In this study, we report that the BET family members Brd2 and Brd4 exert distinct genomic functions at genes whose transcription they co-regulate during mouse T helper 17 (Th17) cell differentiation. Brd2 is associated with the chromatin insulator CTCF and the cohesin complex to support cis-regulatory enhancer assembly for gene transcriptional activation. In this context, Brd2 binds the transcription factor Stat3 in an acetylation-sensitive manner and facilitates Stat3 recruitment to active enhancers occupied with transcription factors Irf4 and Batf. In parallel, Brd4 temporally controls RNA polymerase II (Pol II) processivity during transcription elongation through cyclin T1 and Cdk9 recruitment and Pol II Ser2 phosphorylation. Collectively, our study uncovers both separate and interdependent Brd2 and Brd4 functions in potentiating the genetic program required for Th17 cell development and adaptive immunity.

Original language	English
Pages (from-to)	1068-1080.e5
Journal	Molecular Cell
Volume	65
Issue number	6
DOIs	https://doi.org/10.1016/j.molcel.2016.12.022
State	Published - 16 Mar 2017

Keywords

BRD2
BRD4
CTCF
Th17 cell differentiation
gene transcription
the cohesin complex

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10.1016/j.molcel.2016.12.022

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Cheung, K. L., Zhang, F., Jaganathan, A., Sharma, R., Zhang, Q., Konuma, T., Shen, T., Lee, J. Y., Ren, C., Chen, C. H., Lu, G., Olson, M. R., Zhang, W., Kaplan, M. H., Littman, D. R., Walsh, M. J., Xiong, H., Zeng, L., & Zhou, M. M. (2017). Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation. Molecular Cell, 65(6), 1068-1080.e5. https://doi.org/10.1016/j.molcel.2016.12.022

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title = "Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation",

abstract = "The BET proteins are major transcriptional regulators and have emerged as new drug targets, but their functional distinction has remained elusive. In this study, we report that the BET family members Brd2 and Brd4 exert distinct genomic functions at genes whose transcription they co-regulate during mouse T helper 17 (Th17) cell differentiation. Brd2 is associated with the chromatin insulator CTCF and the cohesin complex to support cis-regulatory enhancer assembly for gene transcriptional activation. In this context, Brd2 binds the transcription factor Stat3 in an acetylation-sensitive manner and facilitates Stat3 recruitment to active enhancers occupied with transcription factors Irf4 and Batf. In parallel, Brd4 temporally controls RNA polymerase II (Pol II) processivity during transcription elongation through cyclin T1 and Cdk9 recruitment and Pol II Ser2 phosphorylation. Collectively, our study uncovers both separate and interdependent Brd2 and Brd4 functions in potentiating the genetic program required for Th17 cell development and adaptive immunity.",

keywords = "BRD2, BRD4, CTCF, Th17 cell differentiation, gene transcription, the cohesin complex",

author = "Cheung, {Ka Lung} and Fan Zhang and Anbalagan Jaganathan and Rajal Sharma and Qiang Zhang and Tsuyoshi Konuma and Tong Shen and Lee, {June Yong} and Chunyan Ren and Chen, {Chih Hung} and Geming Lu and Olson, {Matthew R.} and Weijia Zhang and Kaplan, {Mark H.} and Littman, {Dan R.} and Walsh, {Martin J.} and Huabao Xiong and Lei Zeng and Zhou, {Ming Ming}",

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year = "2017",

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doi = "10.1016/j.molcel.2016.12.022",

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Cheung, KL, Zhang, F, Jaganathan, A, Sharma, R, Zhang, Q, Konuma, T, Shen, T, Lee, JY, Ren, C, Chen, CH, Lu, G, Olson, MR, Zhang, W, Kaplan, MH, Littman, DR, Walsh, MJ, Xiong, H, Zeng, L & Zhou, MM 2017, 'Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation', Molecular Cell, vol. 65, no. 6, pp. 1068-1080.e5. https://doi.org/10.1016/j.molcel.2016.12.022

TY - JOUR

T1 - Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation

AU - Cheung, Ka Lung

AU - Zhang, Fan

AU - Jaganathan, Anbalagan

AU - Sharma, Rajal

AU - Zhang, Qiang

AU - Konuma, Tsuyoshi

AU - Shen, Tong

AU - Lee, June Yong

AU - Ren, Chunyan

AU - Chen, Chih Hung

AU - Lu, Geming

AU - Olson, Matthew R.

AU - Zhang, Weijia

AU - Kaplan, Mark H.

AU - Littman, Dan R.

AU - Walsh, Martin J.

AU - Xiong, Huabao

AU - Zeng, Lei

AU - Zhou, Ming Ming

PY - 2017/3/16

Y1 - 2017/3/16

N2 - The BET proteins are major transcriptional regulators and have emerged as new drug targets, but their functional distinction has remained elusive. In this study, we report that the BET family members Brd2 and Brd4 exert distinct genomic functions at genes whose transcription they co-regulate during mouse T helper 17 (Th17) cell differentiation. Brd2 is associated with the chromatin insulator CTCF and the cohesin complex to support cis-regulatory enhancer assembly for gene transcriptional activation. In this context, Brd2 binds the transcription factor Stat3 in an acetylation-sensitive manner and facilitates Stat3 recruitment to active enhancers occupied with transcription factors Irf4 and Batf. In parallel, Brd4 temporally controls RNA polymerase II (Pol II) processivity during transcription elongation through cyclin T1 and Cdk9 recruitment and Pol II Ser2 phosphorylation. Collectively, our study uncovers both separate and interdependent Brd2 and Brd4 functions in potentiating the genetic program required for Th17 cell development and adaptive immunity.

AB - The BET proteins are major transcriptional regulators and have emerged as new drug targets, but their functional distinction has remained elusive. In this study, we report that the BET family members Brd2 and Brd4 exert distinct genomic functions at genes whose transcription they co-regulate during mouse T helper 17 (Th17) cell differentiation. Brd2 is associated with the chromatin insulator CTCF and the cohesin complex to support cis-regulatory enhancer assembly for gene transcriptional activation. In this context, Brd2 binds the transcription factor Stat3 in an acetylation-sensitive manner and facilitates Stat3 recruitment to active enhancers occupied with transcription factors Irf4 and Batf. In parallel, Brd4 temporally controls RNA polymerase II (Pol II) processivity during transcription elongation through cyclin T1 and Cdk9 recruitment and Pol II Ser2 phosphorylation. Collectively, our study uncovers both separate and interdependent Brd2 and Brd4 functions in potentiating the genetic program required for Th17 cell development and adaptive immunity.

KW - BRD2

KW - BRD4

KW - CTCF

KW - Th17 cell differentiation

KW - gene transcription

KW - the cohesin complex

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U2 - 10.1016/j.molcel.2016.12.022

DO - 10.1016/j.molcel.2016.12.022

M3 - Article

C2 - 28262505

AN - SCOPUS:85014077274

SN - 1097-2765

VL - 65

SP - 1068-1080.e5

JO - Molecular Cell

JF - Molecular Cell

IS - 6

ER -

Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation

Abstract

Keywords

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