ZBED2 is an antagonist of Interferon Regulatory Factor 1 and modifies cell identity in pancreatic cancer (ChIP-seq)

Lineage plasticity is a prominent feature of pancreatic ductal adenocarcinoma (PDA) cells, which can occur via deregulation of lineage-specifying transcription factors. Here, we show that the zinc finger protein ZBED2 is aberrantly expressed in PDA and regulates tumor cell identity in this disease. Unexpectedly, our epigenomic experiments reveal that ZBED2 is a sequence-specific transcriptional repressor of interferon-stimulated genes, which occurs through antagonism of Interferon Regulatory Factor 1 (IRF1)-mediated transcriptional activation at co-occupied promoter elements. Consequently, ZBED2 attenuates the transcriptional output and growth arrest phenotypes downstream of interferon signaling in multiple PDA cell line models. We also found that ZBED2 is preferentially expressed in the squamous molecular subtype of human PDA, in association with inferior patient survival outcomes. Consistent with this observation, we show that ZBED2 can repress the pancreatic progenitor transcriptional program, enhance motility, and promote invasion in PDA cells. Collectively, our findings suggest that high ZBED2 expression is acquired during PDA progression to suppress the interferon response pathway and to promote lineage plasticity in this disease. Overall design: FLAG-ZBED2 ChIP-seq in AsPC1 and SUIT2 cells was performed in FLAG-ZBED2 expressing cells with input genomic DNA as control. IRF1 ChIP-seq was performed using antibody recognizing endogenous protein with input genomic DNA following 12 hours stimulation with IFN-gamma or control and following transduction of empty vector or ZBED2 cDNA.