Nucleosome Engagement Regulates RORγt Structure and Dynamics

Abstract

RORγt is a key transcriptional regulator that supports protective pathogen clearance but also drives autoimmune disorders. Genetic studies have identified RORγt mutations that selectively protect from autoimmunity without compromising host defense. Herein, we describe the molecular principles governing how RORγt selectively drives these context-dependent gene programs. Structural studies revealed the selectivity-determining mutations lie in an α-helix, the C-terminal extension (CTE), which nucleates when RORγt engages partially occluded DNA response elements at nucleosome entry/exit sites. In ex vivo Th17 cells, the CTE is required for full genomic occupancy and expression of inflammatory effector genes, while residual DNA binding supports partial occupancy that, alongside context-dependent transcription factors, induces lineage-stabilizing gene expression. These findings support a model where RORγt uses distinct chromatin binding modes to engage an expansive chromatin landscape to activate target gene programs, explaining the complex phenotypes of CTE mutant mice.