Dynamic regulatory network controlling TH17 cell differentiation

Nir Yosef, Alex K. Shalek, Jellert T. Gaublomme, Hulin Jin, Youjin Lee, Amit Awasthi, Chuan Wu, Katarzyna Karwacz, Sheng Xiao, Marsela Jorgolli, David Gennert, Rahul Satija, Arvind Shakya, Diana Y. Lu, John J. Trombetta, Meenu R. Pillai, Peter J. Ratcliffe, Mathew L. Coleman, Mark Bix, Dean Tantin, Hongkun Park (), Vijay K. Kuchroo () and Aviv Regev ()
Additional contact information
Nir Yosef: Broad Institute of MIT and Harvard, 7 Cambridge Center
Alex K. Shalek: Harvard University
Jellert T. Gaublomme: Harvard University
Hulin Jin: Center for Neurologic Diseases, Brigham & Women’s Hospital, Harvard Medical School
Youjin Lee: Center for Neurologic Diseases, Brigham & Women’s Hospital, Harvard Medical School
Amit Awasthi: Center for Neurologic Diseases, Brigham & Women’s Hospital, Harvard Medical School
Chuan Wu: Center for Neurologic Diseases, Brigham & Women’s Hospital, Harvard Medical School
Katarzyna Karwacz: Center for Neurologic Diseases, Brigham & Women’s Hospital, Harvard Medical School
Sheng Xiao: Center for Neurologic Diseases, Brigham & Women’s Hospital, Harvard Medical School
Marsela Jorgolli: Harvard University
David Gennert: Broad Institute of MIT and Harvard, 7 Cambridge Center
Rahul Satija: Broad Institute of MIT and Harvard, 7 Cambridge Center
Arvind Shakya: University of Utah School of Medicine
Diana Y. Lu: Broad Institute of MIT and Harvard, 7 Cambridge Center
John J. Trombetta: Broad Institute of MIT and Harvard, 7 Cambridge Center
Meenu R. Pillai: St. Jude Children's Research Hospital
Peter J. Ratcliffe: University of Oxford, Headington Campus, Oxford OX3 7BN, UK
Mathew L. Coleman: University of Oxford, Headington Campus, Oxford OX3 7BN, UK
Mark Bix: St. Jude Children's Research Hospital
Dean Tantin: University of Utah School of Medicine
Hongkun Park: Broad Institute of MIT and Harvard, 7 Cambridge Center
Vijay K. Kuchroo: Broad Institute of MIT and Harvard, 7 Cambridge Center
Aviv Regev: Broad Institute of MIT and Harvard, 7 Cambridge Center

Nature, 2013, vol. 496, issue 7446, 461-468

Abstract: 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.

Date: 2013
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DOI: 10.1038/nature11981

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