T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex

Cell Rep. 2016 Jun 21;15(12):2756-70. doi: 10.1016/j.celrep.2016.05.054. Epub 2016 Jun 9.


The transcription factor T-bet directs Th1 cell differentiation, but the molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood. Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator and P-TEFb in the form of the super elongation complex (SEC). Th1 genes are occupied by H3K4me3 and RNA polymerase II in Th2 cells, while T-bet-mediated recruitment of P-TEFb in Th1 cells activates transcriptional elongation. P-TEFb is recruited to both genes and enhancers, where it activates enhancer RNA transcription. P-TEFb inhibition and Mediator and SEC knockdown selectively block activation of T-bet target genes, and P-TEFb inhibition abrogates Th1-associated experimental autoimmune uveitis. T-bet activity is independent of changes in NF-κB RelA and Brd4 binding, with T-bet- and NF-κB-mediated pathways instead converging to allow P-TEFb recruitment. These data provide insight into the mechanism through which lineage-specifying factors promote differentiation of alternative T cell fates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Lineage / genetics
  • Enhancer Elements, Genetic / genetics
  • Gene Expression Regulation*
  • Humans
  • Mice, Inbred C57BL
  • Nuclear Proteins / metabolism
  • Positive Transcriptional Elongation Factor B / metabolism
  • Protein Binding / genetics
  • RNA / genetics
  • RNA / metabolism
  • T-Box Domain Proteins / metabolism*
  • Th1 Cells / metabolism*
  • Th2 Cells / metabolism
  • Transcription Elongation, Genetic*
  • Transcription Factor RelA / metabolism
  • Transcription Factors / metabolism
  • Uveitis / genetics


  • Brd4 protein, mouse
  • Nuclear Proteins
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Transcription Factor RelA
  • Transcription Factors
  • RNA
  • Positive Transcriptional Elongation Factor B