title: Dynamic regulatory network controlling TH17 cell differentiation.
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.
authors: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors: Nir
authors: N
authors: Yosef
authors: Alex K
authors: AK
authors: Shalek
authors: Jellert T
authors: JT
authors: Gaublomme
authors: Hulin
authors: H
authors: Jin
authors: Youjin
authors: Y
authors: Lee
authors: Amit
authors: A
authors: Awasthi
authors: Chuan
authors: C
authors: Wu
authors: Katarzyna
authors: K
authors: Karwacz
authors: Sheng
authors: S
authors: Xiao
authors: Marsela
authors: M
authors: Jorgolli
authors: David
authors: D
authors: Gennert
authors: Rahul
authors: R
authors: Satija
authors: Arvind
authors: A
authors: Shakya
authors: Diana Y
authors: DY
authors: Lu
authors: John J
authors: JJ
authors: Trombetta
authors: Meenu R
authors: MR
authors: Pillai
authors: Peter J
authors: PJ
authors: Ratcliffe
authors: Mathew L
authors: ML
authors: Coleman
authors: Mark
authors: M
authors: Bix
authors: Dean
authors: D
authors: Tantin
authors: Hongkun
authors: H
authors: Park
authors: Vijay K
authors: VK
authors: Kuchroo
authors: Aviv
authors: A
authors: Regev
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks / Q000235:genetics*; D016678:Genome / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D053770:Nanowires; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D012825:Silicon; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D019014:fas Receptor / Q000378:metabolism
chemical_list: C498608:Dsip1 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; C512207:Mina53 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C490424:Pou2af1 protein, mouse; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D019014:fas Receptor; D007371:Interferon-gamma; D004247:DNA; D012825:Silicon