A Validated Regulatory Network for Th17 Cell Specification

SummaryTh17 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.

Graphical AbstractFigure optionsDownload high-quality image (285 K)Download as PowerPoint slideHighlights
► Integrated function of multiple transcription factors in Th17 cell differentiation
► Binding of BATF-IRF4 complexes to DNA mediates chromatin accessibility
► Network-predicted AP-1 factor Fosl2 restricts plasticity of Th17 cells
► Integration of multiple data sets in network most accurately predicts Th17 regulators