期刊
CELL REPORTS
卷 15, 期 12, 页码 2756-2770出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.05.054
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资金
- CRUK - UCL Centre
- Wellcome Trust [WT091009]
- BBSRC [BB/L009277/1]
- MRC Career Development [G0802068]
- MRC [G0400503, G1000758, G953693, MR/M003493/1]
- NIHR UCLH Biomedical Research Centre
- NIHR Clinical Research Facility at Guy's and St. Thomas' NHS Foundation Trust and NIHR Biomedical Research Centre based at Guy's and St. Thomas' NHS Foundation Trust and King's College London
- NIHR Leicester Respiratory Biomedical Research Unit
- BBSRC [BB/L009277/1, BB/L010356/1] Funding Source: UKRI
- MRC [G0400503, G0802068, MR/M003493/1, MR/N006445/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/L009277/1, BB/L010356/1] Funding Source: researchfish
- Medical Research Council [G1000758, G0400503, MR/M003493/1, G0802068, MR/N006445/1] Funding Source: researchfish
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.
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