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

Mol Cell. 2017 Mar 16;65(6):1068-1080.e5. doi: 10.1016/j.molcel.2016.12.022. Epub 2017 Mar 3.

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.

MeSH terms

  • Acetylation
  • Adaptive Immunity*
  • Animals
  • CCCTC-Binding Factor
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Differentiation*
  • Cells, Cultured
  • Chromatin / enzymology*
  • Chromatin / genetics
  • Chromosomal Proteins, Non-Histone / chemistry
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Cyclin T / genetics
  • Cyclin T / metabolism
  • Cyclin-Dependent Kinase 9 / genetics
  • Cyclin-Dependent Kinase 9 / metabolism
  • Gene Expression Regulation
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism
  • Mice, Inbred C57BL
  • Models, Molecular
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phenotype
  • Phosphorylation
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • RNA Interference
  • RNA Polymerase II / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Structure-Activity Relationship
  • Th17 Cells / enzymology*
  • Th17 Cells / immunology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic*
  • Transfection

Substances

  • Brd2 protein, mouse
  • Brd4 protein, mouse
  • CCCTC-Binding Factor
  • Ccnt1 protein, mouse
  • Cell Cycle Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Ctcf protein, mouse
  • Cyclin T
  • Interferon Regulatory Factors
  • Nuclear Proteins
  • Repressor Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Transcription Factors
  • cohesins
  • interferon regulatory factor-4
  • Cdk9 protein, mouse
  • Cyclin-Dependent Kinase 9
  • RNA Polymerase II