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.
Arnulf Hertweck  1 ,  Catherine M Evans  2 ,  Malihe Eskandarpour  3 ,  Jonathan C H Lau  2 ,  Kristine Oleinika  2 ,  Ian Jackson  4 ,  Audrey Kelly  5 ,  John Ambrose  2 ,  Peter Adamson  3 ,  David J Cousins  6 ,  Paul Lavender  5 ,  Virginia L Calder  3 ,  Graham M Lord  7 ,  Richard G Jenner  8
Affiliations
  • 1. UCL Cancer Institute, University College London, 72 Huntley Street, W1T 4JF London, UK; Department of Experimental Immunobiology and NIHR Comprehensive Biomedical Research Centre, Guy's and St. Thomas' Hospital and King's College London, SE1 9RT London, UK.
  • 2. UCL Cancer Institute, University College London, 72 Huntley Street, W1T 4JF London, UK.
  • 3. UCL Institute of Ophthalmology, University College London, EC1V 9EL London, UK.
  • 4. Department of Experimental Immunobiology and NIHR Comprehensive Biomedical Research Centre, Guy's and St. Thomas' Hospital and King's College London, SE1 9RT London, UK.
  • 5. Department of Asthma, Allergy, and Respiratory Science, King's College London, SE1 9RT London, UK.
  • 6. Department of Asthma, Allergy, and Respiratory Science, King's College London, SE1 9RT London, UK; Leicester Institute for Lung Health and Department of Infection, Immunity, and Inflammation, NIHR Leicester Respiratory Biomedical Research Unit, University of Leicester, LE3 9QP Leicester, UK.
  • 7. Department of Experimental Immunobiology and NIHR Comprehensive Biomedical Research Centre, Guy's and St. Thomas' Hospital and King's College London, SE1 9RT London, UK. Electronic address: [email protected].
  • 8. UCL Cancer Institute, University College London, 72 Huntley Street, W1T 4JF London, UK. Electronic address: [email protected].
PMID: 27292648 DOI: 10.1016/j.celrep.2016.05.054
Abstract

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.