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      A validated regulatory network for Th17 cell specification.

      Cell

      metabolism, immunology, cytology, Th17 Cells, Nuclear Receptor Subfamily 1, Group F, Member 3, Molecular Sequence Data, Mice, Knockout, Mice, Interferon Regulatory Factors, Humans, Genome-Wide Association Study, Gene Regulatory Networks, Fos-Related Antigen-2, Encephalomyelitis, Autoimmune, Experimental, Cell Differentiation, Basic-Leucine Zipper Transcription Factors, Animals

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          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. Copyright © 2012 Elsevier Inc. All rights reserved.

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          Author and article information

          Journal
          23021777
          3503487
          10.1016/j.cell.2012.09.016

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