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Dynamic regulatory network controlling TH17 cell differentiation

Author(s)
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; Trombetta, John J.; Pillai, Meenu R.; Ratcliffe, Peter J.; Coleman, Mathew L.; Bix, Mark; Tantin, Dean; Park, Hongkun; Kuchroo, Vijay K.; Regev, Aviv; Lu, Diana; ... Show more Show less
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Alternative title
Dynamic regulatory network controlling T[subscript H]17 cell differentiation
Terms of use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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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 T[subscript H]17 cells, a proinflammatory T-cell subset that has been implicated in the pathogenesis of multiple autoimmune diseases. The T[subscript H]17 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 T[subscript H]17 and other CD4[superscript +] 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 T[subscript H]17 cell differentiation.
Date issued
2013-03
URI
http://hdl.handle.net/1721.1/80821
Department
Massachusetts Institute of Technology. Department of Biology
Journal
Nature
Publisher
Nature Publishing Group
Citation
Yosef, Nir, Alex K. Shalek, Jellert T. Gaublomme, Hulin Jin, Youjin Lee, Amit Awasthi, Chuan Wu, et al. “Dynamic regulatory network controlling TH17 cell differentiation.” Nature 496, no. 7446 (March 6, 2013): 461-468.
Version: Author's final manuscript
ISSN
0028-0836
1476-4687

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