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

• Published in: Nature communications 2023-06, Vol.14 (1), p.3761-3761, Article 3761
• Main Authors: Cobo, Isidoro, Paliwal, Sumit, Bodas, Cristina, Felipe, Irene, Melià-Alomà, Júlia, Torres, Ariadna, Martínez-Villarreal, Jaime, Malumbres, Marina, García, Fernando, Millán, Irene, del Pozo, Natalia, Park, Joo-Cheol, MacDonald, Ray J., Muñoz, Javier, Méndez, Raúl, Real, Francisco X.
• Format: Article
• Language: English
• Subjects: 13; 13/51; 13/89; 38; 38/109; 38/39; 38/77; 38/91; 64/60; 692/4020/1503/1712; 692/4028/67; 82/1; 82/58; 82/80; Acinar cells; Acinar Cells - metabolism; Adenocarcinoma; Animals; Binding sites; Carcinoma, Pancreatic Ductal - pathology; Differentiation; Endoplasmic reticulum; Gene expression; Genes; Humanities and Social Sciences; Humans; Mice; Mice, Knockout; multidisciplinary; Mutants; NFI Transcription Factors - metabolism; Nuclear factor I; Pancreas; Pancreas - metabolism; Pancreatic cancer; Pancreatic Neoplasms - pathology; Pancreatitis; Promoters; Protein metabolism; Protein turnover; Ribonucleic acid; Ribosomes; RNA; rRNA; Science; Science (multidisciplinary); Transcription factors; Tunicamycin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-39291-x

Pancreatic acinar cells rely on PTF1 and other transcription factors to deploy their transcriptional program. We identify NFIC as a NR5A2 interactor and regulator of acinar differentiation. NFIC binding sites are enriched in NR5A2 ChIP-Sequencing peaks. Nfic knockout mice have a smaller, histologically normal, pancreas with reduced acinar gene expression. NFIC binds and regulates the promoters of acinar genes and those involved in RNA/protein metabolism, and Nfic knockout pancreata show defective ribosomal RNA maturation. NFIC dampens the endoplasmic reticulum stress program through binding to gene promoters and is required for resolution of Tunicamycin-mediated stress. NFIC is down-regulated during caerulein pancreatitis and is required for recovery after damage. Normal human pancreata with low levels of NFIC transcripts display reduced expression of genes down-regulated in Nfic knockout mice. NFIC expression is down-regulated in mouse and human pancreatic ductal adenocarcinoma. Consistently, Nfic knockout mice develop a higher number of mutant Kras -driven pre-neoplastic lesions. Pancreatic acinar differentiation can be tumour suppressive for pancreatic ductal adenocarcinoma (PDAC). Here the authors identify nuclear factor I family of transcription factors NFIC as a regulator of pancreatic acinar cell function that restrains mutant KRas-driven pancreas cancer initiation in mice.