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

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
Mol Cell 65 1068-1080.e5 (2017)
Cited: 66 times
EuropePMC logo PMID: 28262505

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.

Articles - 5u5s mentioned but not cited (2)

  1. Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation. 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. Mol Cell 65 1068-1080.e5 (2017)
  2. Discovery of new STAT3 inhibitors as anticancer agents using ligand-receptor contact fingerprints and docking-augmented machine learning. Jaradat NJ, Alshaer W, Hatmal M, Taha MO. RSC Adv 13 4623-4640 (2023)


Reviews citing this publication (13)

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Articles citing this publication (51)

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  29. Bromodomain and extra-terminal domain (BET) proteins regulate melanocyte differentiation. Trivedi A, Mehrotra A, Baum CE, Lewis B, Basuroy T, Blomquist T, Trumbly R, Filipp FV, Setaluri V, de la Serna IL. Epigenetics Chromatin 13 14 (2020)
  30. PD-L1 is upregulated via BRD2 in head and neck squamous cell carcinoma models of acquired cetuximab resistance. Bhola NE, Njatcha C, Hu L, Lee ED, Shiah JV, Kim MO, Johnson DE, Grandis JR. Head Neck 43 3364-3373 (2021)
  31. The Bromodomain Containing 8 (BRD8) transcriptional network in human lung epithelial cells. Browne JA, NandyMazumdar M, Paranjapye A, Leir SH, Harris A. Mol Cell Endocrinol 524 111169 (2021)
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  33. Dissecting the Role of BET Bromodomain Proteins BRD2 and BRD4 in Human NK Cell Function. Cribbs AP, Filippakopoulos P, Philpott M, Wells G, Penn H, Oerum H, Valge-Archer V, Feldmann M, Oppermann U. Front Immunol 12 626255 (2021)
  34. Involvement of RUNX and BRD Family Members in Restriction Point. Lee JW, Park TG, Bae SC. Mol Cells 42 836-839 (2019)
  35. MACMIC Reveals A Dual Role of CTCF in Epigenetic Regulation of Cell Identity Genes. Wang G, Xia B, Zhou M, Lv J, Zhao D, Li Y, Bu Y, Wang X, Cooke JP, Cao Q, Lee MG, Zhang L, Chen K. Genomics Proteomics Bioinformatics 19 140-153 (2021)
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  47. The Role of Bromodomain and Extraterminal (BET) Proteins in Controlling the Phagocytic Activity of Microglia In Vitro: Relevance to Alzheimer's Disease. Matuszewska M, Cieślik M, Wilkaniec A, Strawski M, Czapski GA. Int J Mol Sci 24 13 (2022)
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  49. Disabled C3ar1/C5ar1 Signaling in Foxp3+ T Regulatory Cells Leads to TSDR Demethylation and Long-Term Stability. Medof ME, Rieder SA, Shevach EM. J Immunol 211 1359-1366 (2023)
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