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

Abstract

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.

Transcriptome analysis of the response to thyroid hormone in Xenopus neural stem and progenitor cells

“…30 These factors are important regulators of stem cell function and nfia and nfib loss-of-function result in delayed glial and neuronal differentiation in mice. 30 Although no specific role of nfic has been determined in the CNS, a recent work shows that NFIC regulates ribosomal biology in pancreatic acinar cells, 31 which is interesting considering the results that will be discussed later. Mat2a catalyzes the synthesis of the S-adenosylmethionine (SAM), which is critical to regulate the maintenance and differentiation of mammal stem and cancer cells.…”

ZDHHC20-mediated S-palmitoylation of YTHDF3 stabilizes MYC mRNA to promote pancreatic cancer progression

“…Moreover, due to the lack of early disease diagnosis and the tendency of PDAC to metastasize and drug resistance, the mortality of PDAC is almost equal to its morbidity 3 . Oncogenic KRAS mutations are initiating events in pancreatic tumorigenesis, and these mutations, most commonly KRAS G12D, occur in more than 90% of pancreatic intraepithelial neoplasias (PanINs) [4][5][6][7] . Genetic control of malignant transformation and tumor maintenance in PDAC in the context of KRAS signaling remains largely unexplored 8 .…”