期刊
CELL
卷 151, 期 2, 页码 289-303出版社
CELL PRESS
DOI: 10.1016/j.cell.2012.09.016
关键词
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资金
- NIH [RC1 AI087266, RC4 AI092765, PN2 EY016586, IU54CA143907-01, EY016586-06]
- NSF [IOS-1126971]
- Leukemia and Lymphoma Society
- Crohn's and Colitis Foundation of America
- National Arthritis Research Foundation
- Cancer Research Institute
Th17 cells have critical roles in mucosal defense and are major contributors to inflammatory disease. Their differentiation requires the nuclear hormone receptor ROR gamma t working with multiple other essential transcription factors (TFs). We have used an iterative systems approach, combining genome-wide TF occupancy, expression profiling of TF mutants, and expression time series to delineate the Th17 global transcriptional regulatory network. We find that cooperatively bound BATF and IRF4 contribute to initial chromatin accessibility and, with STAT3, initiate a transcriptional program that is then globally tuned by the lineage-specifying TF ROR gamma t, which plays a focal deterministic role at key loci. Integration of multiple data sets allowed inference of an accurate predictive model that we computationally and experimentally validated, identifying multiple new Th17 regulators, including Fosl2, a key determinant of cellular plasticity. This interconnected network can be used to investigate new therapeutic approaches to manipulate Th17 functions in the setting of inflammatory disease.
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