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

被引：47

作者：

Hertweck, Arnulf ^{[1
,2
,3
,4
]}

Evans, Catherine M. ^{[1
]}

Eskandarpour, Malihe ^{[5
]}

Lau, Jonathan C. H. ^{[1
]}

Oleinika, Kristine ^{[1
]}

Jackson, Ian ^{[2
,3
,4
]}

Kelly, Audrey ^{[6
]}

Ambrose, John ^{[1
]}

Adamson, Peter ^{[5
]}

Cousins, David J. ^{[6
,7
,8
]}

Lavender, Paul ^{[6
]}

Calder, Virginia L. ^{[5
]}

Lord, Graham M. ^{[2
,3
,4
]}

Jenner, Richard G. ^{[1
]}

机构：

[1] UCL, UCL Canc Inst, 72 Huntley St, London W1T 4JF, England

[2] Guys & St Thomas Hosp, Dept Expt Immunobiol, London SE1 9RT, England

[3] Guys & St Thomas Hosp, NIHR Comprehens Biomed Res Ctr, London SE1 9RT, England

[4] Kings Coll London, London SE1 9RT, England

[5] UCL, UCL Inst Ophthalmol, London EC1V 9EL, England

[6] Kings Coll London, Dept Asthma Allergy & Resp Sci, London SE1 9RT, England

[7] Univ Leicester, Leicester Inst Lung Hlth, Leicester LE3 9QP, Leics, England

[8] Univ Leicester, Dept Infect Immun & Inflammat, NIHR Leicester Resp Biomed Res Unit, Leicester LE3 9QP, Leics, England

来源：

CELL REPORTS | 2016年 / 15卷 / 12期

基金：

英国惠康基金; 英国生物技术与生命科学研究理事会;

关键词：

NF-KAPPA-B; RNA-POLYMERASE-II; DISTAL REGULATORY ELEMENTS; BROMODOMAIN PROTEIN BRD4; TRANSCRIPTIONAL ELONGATION; CELL IDENTITY; P-TEFB; SELECTIVE-INHIBITION; LINEAGE COMMITMENT; INTERFERON-GAMMA;

D O I：

10.1016/j.celrep.2016.05.054

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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-kB RelA and Brd4 binding, with T-bet-and NF-kB-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.

引用

页码：2756 / 2770

页数：15

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