title: A validated regulatory network for Th17 cell specification.
abstract: Th17 cells have critical roles in mucosal defense and are major contributors to inflammatory disease. Their differentiation requires the nuclear hormone receptor RORγt working with multiple other essential transcription factors (TFs). We have used an iterative systems approach, combining genome-wide TF occupancy, expression profiling of TF mutants, and expression time series to delineate the Th17 global transcriptional regulatory network. We find that cooperatively bound BATF and IRF4 contribute to initial chromatin accessibility and, with STAT3, initiate a transcriptional program that is then globally tuned by the lineage-specifying TF RORγt, which plays a focal deterministic role at key loci. Integration of multiple data sets allowed inference of an accurate predictive model that we computationally and experimentally validated, identifying multiple new Th17 regulators, including Fosl2, a key determinant of cellular plasticity. This interconnected network can be used to investigate new therapeutic approaches to manipulate Th17 functions in the setting of inflammatory disease.
authors.affiliation: Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Ciofani
authors.forename: Aviv
authors.initials: A
authors.lastname: Madar
authors.forename: Carolina
authors.initials: C
authors.lastname: Galan
authors.forename: Maclean
authors.initials: M
authors.lastname: Sellars
authors.forename: Kieran
authors.initials: K
authors.lastname: Mace
authors.forename: Florencia
authors.initials: F
authors.lastname: Pauli
authors.forename: Ashish
authors.initials: A
authors.lastname: Agarwal
authors.forename: Wendy
authors.initials: W
authors.lastname: Huang
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Parkhurst
authors.forename: Michael
authors.initials: M
authors.lastname: Muratet
authors.forename: Kim M
authors.initials: KM
authors.lastname: Newberry
authors.forename: Sarah
authors.initials: S
authors.lastname: Meadows
authors.forename: Alex
authors.initials: A
authors.lastname: Greenfield
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Preti
authors.initials: P
authors.lastname: Jain
authors.forename: Francis K
authors.initials: FK
authors.lastname: Kirigin
authors.forename: Carmen
authors.initials: C
authors.lastname: Birchmeier
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.forename: Richard
authors.initials: R
authors.lastname: Bonneau
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D002454:Cell Differentiation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D051921:Fos-Related Antigen-2 / Q000276:immunology / Q000378:metabolism; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D000099218:Interferon Regulatory Factor-4
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D051921:Fos-Related Antigen-2; D050835:Interferon Regulatory Factors; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D000099218:Interferon Regulatory Factor-4; C431772:Batf protein, mouse; C497872:FOSL2 protein, human; C497873:Fosl2 protein, mouse