ZBED2 is an antagonist of Interferon Regulatory Factor 1 and modifies cell identity in pancreatic cancer (RNA-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: For RNA-seq performed following ZBED2 or IRF1 knock out in PDA cells, two independent sgRNAs targeting the DNA binding domain of each factor were used a technical repeats. For RNA-seq performed following IRF1 cDNA expression in AsPC1 cells, two biological repeats were analyzed. For RNA-seq performed following ZBED2 cDNA expression in 15 human PDA cell lines, 1 technical repeat for each cell line was used. For RNA-seq performed following treatment of AsPC1-empty and AsPC1-ZBED2 cells with IFN-beta, IFN-gamma or control, two biological repeats were used for each condition.