Dynamic regulatory network controlling TH17 cell differentiation.
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Abstract | Despite their importance, the molecular circuits that control the differentiation of naive T cells remain largely unknown. Recent studies that reconstructed regulatory networks in mammalian cells have focused on short-term responses and relied on perturbation-based approaches that cannot be readily applied to primary T cells. Here we combine transcriptional profiling at high temporal resolution, novel computational algorithms, and innovative nanowire-based perturbation tools to systematically derive and experimentally validate a model of the dynamic regulatory network that controls the differentiation of mouse TH17 cells, a proinflammatory T-cell subset that has been implicated in the pathogenesis of multiple autoimmune diseases. The TH17 transcriptional network consists of two self-reinforcing, but mutually antagonistic, modules, with 12 novel regulators, the coupled action of which may be essential for maintaining the balance between TH17 and other CD4(+) T-cell subsets. Our study identifies and validates 39 regulatory factors, embeds them within a comprehensive temporal network and reveals its organizational principles; it also highlights novel drug targets for controlling TH17 cell differentiation. |
Year of Publication | 2013
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Journal | Nature
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Volume | 496
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Issue | 7446
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Pages | 461-8
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Date Published | 2013 Apr 25
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ISSN | 1476-4687
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URL | |
DOI | 10.1038/nature11981
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PubMed ID | 23467089
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PubMed Central ID | PMC3637864
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Links | |
Grant list | R01 NS030843 / NS / NINDS NIH HHS / United States
NS 30843 / NS / NINDS NIH HHS / United States
F32 HD075541 / HD / NICHD NIH HHS / United States
5DP1OD003893-03 / OD / NIH HHS / United States
R01 NS045937 / NS / NINDS NIH HHS / United States
K01 DK090105 / DK / NIDDK NIH HHS / United States
DP1OD003958-01 / OD / NIH HHS / United States
RG/11/1/28684 / British Heart Foundation / United Kingdom
R37 NS030843 / NS / NINDS NIH HHS / United States
P50 HG006193 / HG / NHGRI NIH HHS / United States
AI073748 / AI / NIAID NIH HHS / United States
P01 AI045757 / AI / NIAID NIH HHS / United States
Howard Hughes Medical Institute / United States
DP1 OD003893 / OD / NIH HHS / United States
1P50HG006193-01 / HG / NHGRI NIH HHS / United States
NS045937 / NS / NINDS NIH HHS / United States
P01 AI073748 / AI / NIAID NIH HHS / United States
R01 AI100873 / AI / NIAID NIH HHS / United States
R29 NS030843 / NS / NINDS NIH HHS / United States
AI45757 / AI / NIAID NIH HHS / United States
DP1 OD003958 / OD / NIH HHS / United States
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