T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex.
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.
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.
Arnulf
A
Hertweck
UCL Cancer Institute, University College London, 72 Huntley Street, W1T 4JF London, UK.
Catherine M
CM
Evans
UCL Institute of Ophthalmology, University College London, EC1V 9EL London, UK.
Malihe
M
Eskandarpour
UCL Cancer Institute, University College London, 72 Huntley Street, W1T 4JF London, UK.
Jonathan C H
JC
Lau
UCL Cancer Institute, University College London, 72 Huntley Street, W1T 4JF London, UK.
Kristine
K
Oleinika
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.
Ian
I
Jackson
Department of Asthma, Allergy, and Respiratory Science, King's College London, SE1 9RT London, UK.
Audrey
A
Kelly
UCL Cancer Institute, University College London, 72 Huntley Street, W1T 4JF London, UK.
John
J
Ambrose
UCL Institute of Ophthalmology, University College London, EC1V 9EL London, UK.
Peter
P
Adamson
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.
David J
DJ
Cousins
Department of Asthma, Allergy, and Respiratory Science, King's College London, SE1 9RT London, UK.
Paul
P
Lavender
UCL Institute of Ophthalmology, University College London, EC1V 9EL London, UK.
Virginia L
VL
Calder
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: graham.lord@kcl.ac.uk.
Graham M
GM
Lord
UCL Cancer Institute, University College London, 72 Huntley Street, W1T 4JF London, UK. Electronic address: r.jenner@ucl.ac.uk.
Richard G
RG
Jenner
D000818:Animals; D019070:Cell Lineage / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism; D061805:Transcription Elongation, Genetic; D051996:Transcription Factor RelA / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014605:Uveitis / Q000235:genetics; D000098815:T-bet Transcription Factor; D000092468:Bromodomain Containing Proteins
D009687:Nuclear Proteins; D042925:Positive Transcriptional Elongation Factor B; D012313:RNA; D020825:T-Box Domain Proteins; D051996:Transcription Factor RelA; D014157:Transcription Factors; D000098815:T-bet Transcription Factor; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins