A validated regulatory network for Th17 cell specification

Cell. 2012 Oct 12;151(2):289-303. doi: 10.1016/j.cell.2012.09.016. Epub 2012 Sep 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

  • Basic-Leucine Zipper Transcription Factors
  • Batf protein, mouse
  • FOSL2 protein, human
  • Fos-Related Antigen-2
  • Fosl2 protein, mouse
  • Interferon Regulatory Factors
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • interferon regulatory factor-4

Associated data

  • GEO/GSE40918