T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex
Arnulf Hertweck,
Catherine M. Evans,
Malihe Eskandarpour,
Jonathan C.H. Lau,
Kristine Oleinika,
Ian Jackson,
Audrey Kelly,
John Ambrose,
Peter Adamson,
David J. Cousins,
Paul Lavender,
Virginia L. Calder,
Graham M. Lord,
Richard G. Jenner
Affiliations
Arnulf Hertweck
UCL Cancer Institute, University College London, 72 Huntley Street, W1T 4JF London, UK
Catherine M. Evans
UCL Cancer Institute, University College London, 72 Huntley Street, W1T 4JF London, UK
Malihe Eskandarpour
UCL Institute of Ophthalmology, University College London, EC1V 9EL London, UK
Jonathan C.H. Lau
UCL Cancer Institute, University College London, 72 Huntley Street, W1T 4JF London, UK
Kristine Oleinika
UCL Cancer Institute, University College London, 72 Huntley Street, W1T 4JF London, UK
Ian Jackson
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
Audrey Kelly
Department of Asthma, Allergy, and Respiratory Science, King’s College London, SE1 9RT London, UK
John Ambrose
UCL Cancer Institute, University College London, 72 Huntley Street, W1T 4JF London, UK
Peter Adamson
UCL Institute of Ophthalmology, University College London, EC1V 9EL London, UK
David J. Cousins
Department of Asthma, Allergy, and Respiratory Science, King’s College London, SE1 9RT London, UK
Paul Lavender
Department of Asthma, Allergy, and Respiratory Science, King’s College London, SE1 9RT London, UK
Virginia L. Calder
UCL Institute of Ophthalmology, University College London, EC1V 9EL London, UK
Graham M. Lord
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
Richard G. Jenner
UCL Cancer Institute, University College London, 72 Huntley Street, W1T 4JF London, UK
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.
