Yosef, NirShalek, Alex K.Gaublomme, JellertJin, HulinLee, YoujinAwasthi, AmitWu, ChuanKarwacz, KatarzynaXiao, ShengJorgolli, MarselaGennert, DavidSatija, RahulShakya, ArvindLu, Diana Y.Trombetta, John J.Pillai, Meenu R.Ratcliffe, Peter J.Coleman, Mathew L.Bix, MarkTantin, DeanPark, HongkunKuchroo, VijayRegev, Aviv2014-03-102013Yosef, N., A. K. Shalek, J. T. Gaublomme, H. Jin, Y. Lee, A. Awasthi, C. Wu, et al. 2013. “Dynamic regulatory network controlling Th17 cell differentiation.” Nature 496 (7446): 461-468. doi:10.1038/nature11981. http://dx.doi.org/10.1038/nature11981.0028-0836http://nrs.harvard.edu/urn-3:HUL.InstRepos:11878808Despite their importance, the molecular circuits that control the differentiation of naïve 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 tools for performing perturbations in primary T cells to systematically derive and experimentally validate a model of the dynamic regulatory network that controls Th17 differentiation. The network consists of two self-reinforcing, but mutually antagonistic, modules, with 12 novel regulators, whose coupled action may be essential for maintaining the balance between Th17 and other CD4+ T cell subsets. Overall, our study identifies and validates 39 regulatory factors, embeds them within a comprehensive temporal network and reveals its organizational principles, and highlights novel drug targets for controlling Th17 differentiation.en-USJournal Article2014-03-1010.1038/nature11981