A validated regulatory network for Th17 cell specification

Maria Ciofani, Aviv Madar, Carolina Galan, MacLean Sellars, Kieran MacE, Florencia Pauli, Ashish Agarwal, Wendy Huang, Christopher N. Parkurst, Michael Muratet, Kim M. Newberry, Sarah Meadows, Alex Greenfield, Yi Yang, Preti Jain, Francis K. Kirigin, Carmen Birchmeier, Erwin F. Wagner, Kenneth M. Murphy, Richard M. MyersRichard Bonneau, Dan R. Littman

Research output: Contribution to journalArticlepeer-review

610 Scopus citations

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.

Original languageEnglish
Pages (from-to)289-303
Number of pages15
JournalCell
Volume151
Issue number2
DOIs
StatePublished - Oct 12 2012

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