Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas

Chronic inflammation increases the risk of several cancer types. The current notion is that the control of inflammatory responses relies on transcriptional networks distinct from those involved in cell differentiation (1–3). The orphan nuclear receptor NR5A2 participates in a wide variety of processes including cholesterol and glucose metabolism in the liver, resolution of ER stress, intestinal glucocorticoid production, pancreatic development, and acinar differentiation (4–8). Single nucleotide polymorphisms (SNPs) in the vicinity of NR5A2 have been associated with the risk of pancreatic adenocarcinoma (PDAC) through genome wide association studies (9,10). In mice, Nr5a2 heterozygosity sensitizes the pancreas to damage, impairs regeneration, and cooperates with mutant KRas in tumor progression (11). Through global transcriptomic analysis, we describe here an epithelial cell-autonomous basal pre-inflammatory state in the pancreas of Nr5a2(+/−) mice that is reminiscent of early stages of pancreatitis-induced inflammation and is conserved in histologically normal human pancreata with reduced NR5A2 mRNA expression. In Nr5a2(+/−) mice, Nr5a2 undergoes a dramatic transcriptional switch relocating from differentiation-specific to inflammatory genes thereby promoting AP-1-dependent gene transcription. Pancreatic deletion of c-Jun rescues the pre-inflammatory phenotype, Nr5a2 binding to inflammatory gene promoters, and the defective regenerative response to damage. These findings support the notion that, in the pancreas, the same transcriptional networks involved in differentiation-specific functions suppress inflammatory programmes. These networks can be subverted to foster inflammation upon genetic or environmental constraints.