Epigenetic dependencies of interferon gamma-induced gene expression [ATAC-Seq]

Interferon gamma (IFNy) is a pro-inflammatory cytokine that directly activates the JAK/STAT pathway. However, the temporal dynamics of chromatin remodeling and transcriptional activation initiated by IFNy have not been systematically profiled in an unbiased manner. Herein, we integrated transcriptomic and epigenomic profiling to characterize the acute epigenetic changes induced by IFNy stimulation in a murine breast cancer model. We identified de novo activation of cis-regulatory elements bound by Irf1 that were characterized by increased chromatin accessibility, differential usage of pro-inflammatory enhancers, and downstream recruitment of BET proteins and RNA polymerase II. To functionally validate this hierarchical model of IFNy-driven transcription, we applied selective antagonists of histone acetyltransferases P300/CBP or acetyl-lysine readers of the BET family. This highlighted that histone acetylation is an antecedent event in IFNy-driven transcription, whereby targeting of P300/CBP but not BET inhibition, could curtail the epigenetic remodeling induced by IFNy through suppression of Irf1 transactivation. These data highlight the utility for epigenetic therapies to reprogram pro-inflammatory gene expression, which may have therapeutic implications for anti-tumor immunity and inflammatory diseases. Overall design: Examination of changes in chromatin accessability by ATAC-seq following stimulation of AT3 cells treated in technical duplicate with interferon gamma (IFNy) alone and in combination with catalytic inhibition of P300/CBP for 3 hours.