Dynamic regulatory network controlling TH17 cell differentiation.

Nature
Authors
Keywords
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
Journal
Nature
Volume
496
Issue
7446
Pages
461-8
Date Published
2013 Apr 25
ISSN
1476-4687
URL
DOI
10.1038/nature11981
PubMed ID
23467089
PubMed Central ID
PMC3637864
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