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Nature DOI:10.1038/nature11981

Dynamic regulatory network controlling TH17 cell differentiation.

Publication TypeJournal Article
Year of Publication2013
AuthorsYosef, N, Shalek, AK, Gaublomme, JT, Jin, H, Lee, Y, Awasthi, A, Wu, C, Karwacz, K, Xiao, S, Jorgolli, M, Gennert, D, Satija, R, Shakya, A, Lu, DY, Trombetta, JJ, Pillai, MR, Ratcliffe, PJ, Coleman, ML, Bix, M, Tantin, D, Park, H, Kuchroo, VK, Regev, A
JournalNature
Volume496
Issue7446
Pages461-8
Date Published2013 Apr 25
ISSN1476-4687
KeywordsAnimals, Antigens, CD95, Cell Differentiation, Cells, Cultured, DNA, Forkhead Transcription Factors, Gene Knockdown Techniques, Gene Regulatory Networks, Genome, Interferon-gamma, Interleukin-2, Mice, Mice, Inbred C57BL, Nanowires, Neoplasm Proteins, Nuclear Proteins, Reproducibility of Results, RNA, Messenger, Silicon, Th17 Cells, Time Factors, Trans-Activators, Transcription Factors, Transcription, Genetic
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.

URLhttp://dx.doi.org/10.1038/nature11981
DOI10.1038/nature11981
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23467089?dopt=Abstract

Alternate JournalNature
PubMed ID23467089
PubMed Central IDPMC3637864
Grant ListR01 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