|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Yosef, 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|
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.