Dynamic regulatory network controlling TH17 cell differentiation

N. Yosef, A. K. Shalek, J. T. Gaublomme, H. Jin, Y. Lee, A. Awasthi, C. Wu, K. Karwacz, S. Xiao, M. Jorgolli, D. Gennert, R. Satija, A. Shakya, D. Y. Lu, J. J. Trombetta, M. R. Pillai, P. J. Ratcliffe, M. L. Coleman, M. Bix, D. TantinH. Park, V. K. Kuchroo, A. Regev

Research output: Contribution to journalArticlepeer-review


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.
Original languageUndefined
Pages (from-to)461-8
Issue number7446
StatePublished - 2013


  • 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

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