Publication Date:
2013-03-08
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637864/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637864/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yosef, Nir -- Shalek, Alex K -- Gaublomme, Jellert T -- Jin, Hulin -- Lee, Youjin -- Awasthi, Amit -- Wu, Chuan -- Karwacz, Katarzyna -- Xiao, Sheng -- Jorgolli, Marsela -- Gennert, David -- Satija, Rahul -- Shakya, Arvind -- Lu, Diana Y -- Trombetta, John J -- Pillai, Meenu R -- Ratcliffe, Peter J -- Coleman, Mathew L -- Bix, Mark -- Tantin, Dean -- Park, Hongkun -- Kuchroo, Vijay K -- Regev, Aviv -- 1P50HG006193-01/HG/NHGRI NIH HHS/ -- 5DP1OD003893-03/OD/NIH HHS/ -- AI073748/AI/NIAID NIH HHS/ -- AI45757/AI/NIAID NIH HHS/ -- DP1 OD003893/OD/NIH HHS/ -- DP1 OD003958/OD/NIH HHS/ -- DP1OD003958-01/OD/NIH HHS/ -- F32 HD075541/HD/NICHD NIH HHS/ -- K01 DK090105/DK/NIDDK NIH HHS/ -- NS 30843/NS/NINDS NIH HHS/ -- NS045937/NS/NINDS NIH HHS/ -- P01 AI045757/AI/NIAID NIH HHS/ -- P01 AI073748/AI/NIAID NIH HHS/ -- P50 HG006193/HG/NHGRI NIH HHS/ -- R01 AI100873/AI/NIAID NIH HHS/ -- R01 NS030843/NS/NINDS NIH HHS/ -- R01 NS045937/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Apr 25;496(7446):461-8. doi: 10.1038/nature11981. Epub 2013 Mar 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23467089" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antigens, CD95/metabolism
;
Cell Differentiation/*genetics
;
Cells, Cultured
;
DNA/genetics/metabolism
;
Forkhead Transcription Factors/metabolism
;
Gene Knockdown Techniques
;
Gene Regulatory Networks/*genetics
;
Genome/genetics
;
Interferon-gamma/biosynthesis
;
Interleukin-2/genetics
;
Mice
;
Mice, Inbred C57BL
;
Nanowires
;
Neoplasm Proteins/metabolism
;
Nuclear Proteins/metabolism
;
RNA, Messenger/genetics/metabolism
;
Reproducibility of Results
;
Silicon
;
Th17 Cells/*cytology/immunology/*metabolism
;
Time Factors
;
Trans-Activators/metabolism
;
Transcription Factors/metabolism
;
Transcription, Genetic/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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