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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27 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 languageEnglish (US)
Pages (from-to)1068-1080.e5
JournalMolecular Cell
Volume65
Issue number6
DOIs
StatePublished - Mar 16 2017

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Keywords

  • BRD2
  • BRD4
  • CTCF
  • Th17 cell differentiation
  • gene transcription
  • the cohesin complex

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

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