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 TantinHongkun Park, Vijay K Kuchroo, Aviv Regev

Research output: Contribution to journalArticlepeer-review

429 Citations (Scopus)


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 languageEnglish
Pages (from-to)461–468
Issue number7446
Early online date6 Mar 2013
Publication statusPublished - 25 Apr 2013


  • Animals
  • Antigens, CD95
  • Cell Differentiation
  • Cells, Cultured
  • DNA
  • Forkhead Transcription Factors
  • Gene Knockdown Techniques
  • Gene Regulatory Networks
  • Genome
  • Interferon-gamma
  • Interleukin-2
  • Mice
  • Mice, Inbred C57BL
  • Nanowires
  • Neoplasm Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • Reproducibility of Results
  • Silicon
  • Th17 Cells
  • Time Factors
  • Trans-Activators
  • Transcription Factors
  • Transcription, Genetic


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