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

Chang, Y.; Mata-Garrido, J.; desterke, C.; Batsche, E.; Hamai, A.; Youssouf, S.; Skurnik, D.; Jalil, A.; Beche, J.-C.; Piaggio, E.; Arbibe, L.; Marchand, Y. C.

doi:10.1101/2022.12.27.522038

bioRxiv · 10.1101/2022.12.27.522038

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

Chang, Y.·Mata-Garrido, J.·desterke, C.·Batsche, E.·Hamai, A.·Youssouf, S.·Skurnik, D.·Jalil, A.·Beche, J.-C.·Piaggio, E.·Arbibe, L.·Marchand, Y. C.

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Abstract

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.

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Chang, Y., Mata-Garrido, J., desterke, C., Batsche, E., Hamai, A., Youssouf, S., Skurnik, D., Jalil, A., Beche, J.-C., Piaggio, E., Arbibe, L., Marchand, Y. C.. 2022-12-27. The HP1γ epigenetic silencer dampens IFN-γ response at the gut epithelial barrier. https://doi.org/10.1101/2022.12.27.522038

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