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A validated regulatory network for Th17 cell specification

Item Type:Article
Title:A validated regulatory network for Th17 cell specification
Creators Name:Ciofani, M. and Madar, A. and Galan, C. and Sellars, M. and Mace, K. and Pauli, F. and Agarwal, A. and Huang, W. and Parkurst, C.N. and Muratet, M. and Newberry, K.M. and Meadows, S. and Greenfield, A. and Yang, Y. and Jain, P. and Kirigin, F.K. and Birchmeier, C. and Wagner, E.F. and Murphy, K.M. and Myers, R.M. and Bonneau, R. and Littman, D.R.
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.
Keywords:Basic-Leucine Zipper Transcription Factors, Cell Differentiation, Experimental Autoimmune Encephalomyelitis, Fos-Related Antigen-2, Gene Regulatory Networks, Genome-Wide Association Study, Interferon Regulatory Factors, Knockout Mice, Member 3 Group F Nuclear Receptor Subfamily 1, Molecular Sequence Data, Th17 Cells, Animals, Mice
Publisher:Cell Press
Page Range:289-303
Date:12 October 2012
Official Publication:https://doi.org/10.1016/j.cell.2012.09.016
PubMed:View item in PubMed

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