NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and suppresses PDAC initiation

Tissue-specific differentiation is driven by specialized transcriptional networks. Pancreatic acinar cells crucially rely on the PTF1 complex, and on additional transcription factors, to deploy their transcriptional program. Here, we identify NFIC as a novel regulator of acinar differentiation using a variety of methodological strategies. NFIC binding sites are found at very short distances from NR5A2-bound genomic regions and both proteins co-occur in the same complex. Nfic knockout mice show reduced expression of acinar genes and, in ChIP-seq experiments, NFIC binds the promoters of acinar genes. In addition, NFIC binds to the promoter of, and regulates, genes involved in RNA and protein metabolism; in Nfic knockout mice, p-RS6K1 and p-IEF4E are down-regulated indicating reduced activity of the mTOR pathway. In 266-6 acinar cells, NFIC dampens the ER stress program through its binding to ER stress gene promoters and is required for complete resolution of Tunicamycin-mediated ER stress. Normal human pancreata from subjects with low NFIC mRNA levels display reduced epxression of genes down-regulated in Nfic knockout mice. Consistently, NFIC displays reduced expression upon induced acute pancreatitis and is required for proper recovery after damage. Finally, expression of NFIC is lower in samples of mouse and human pancreatic ductal adenocarcinoma and Nfic knockout mice develop an increased number of mutant Kras -driven pre-neoplastic lesions. ### Competing Interest Statement The authors have declared no competing interest. * ChIP : chromatin immunoprecipitation DEG : differentially expressed genes EMT : epithelial-mesenchymal transition ER : endoplasmic reticulum GSEA : Gene set enrichment analysis IF : immunofluorescence IHC : immunohistochemistry PDAC : pancreatic ductal adenocarcinoma TF : transcription factor TM : tunicamycin UPR : unfolded protein response