The HP1γ epigenetic silencer dampens IFN-γ response at the gut epithelial barrier

Interferon gamma (IFN-{gamma}) plays central roles in the pathophysiology of inflammatory bowel disease (IBD), both activating inflammatory responses and immunosuppressive functions. However, the epigenetic mechanisms controlling the expression of IFN-{gamma} responsive genes at the gut epithelial barrier are not well understood. In this study, we identified the epigenetic regulator HP1{gamma} as a transcriptional repressor of the IFN-{gamma}-responsive genes STAT1 (signal transducer and activator of transcription 1) and PD-L1 (Programmed Cell Death Ligand 1). Accordingly, HP1{gamma} gene inactivation in the mouse gut epithelium resulted in an immunopathology with a long-lasting up-regulation of STAT1 and PD-L1. Colon organoids models and in vitro cell lines showed that HP1{gamma} deficiency primed STAT1 and PD-L1 expressions, ultimately sensitizing epithelial cells to IFN-{gamma} stimulation. Chromatin immunoprecipitation experiments suggest that HP1 promoter tethering is involved in the silencing of gene expression. Overall, these results identify HP1{gamma} as an epigenetic silencing pathway controlling the IFN-{gamma} response at the epithelial barrier.