LRH-1 and PTF1-L coregulate an exocrine pancreas-specific transcriptional network for digestive function

Abstract

We have determined the cistrome and transcriptome for the nuclear receptor liver receptor homolog-1 (LRH-1) in exocrine pancreas. Chromatin immunoprecipitation (ChIP)-seq and RNA-seq analyses reveal that LRH-1 directly induces expression of genes encoding digestive enzymes and secretory and mitochondrial proteins. LRH-1 cooperates with the pancreas transcription factor 1-L complex (PTF1-L) in regulating exocrine pancreas-specific gene expression. Elimination of LRH-1 in adult mice reduced the concentration of several lipases and proteases in pancreatic fluid and impaired pancreatic fluid secretion in response to cholecystokinin. Thus, LRH-1 is a key regulator of the exocrine pancreas-specific transcriptional network required for the production and secretion of pancreatic fluid.

The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell formation and acinar differentiation during pancreatic organogenesis

“…In the adult pancreas, NR5A2 collaborates with PTF1A to control exocrine genes (Holmstrom et al, 2011). PTF1A is a class B bHLH transcription factor restricted to the pancreas, selected regions of the neural tube, retina and the cerebellum.…”

“…NR5A2 activity is modulated by phosphorylation and sumoylation (Lee et al, 2006;Venteclef et al, 2010) and through interaction with co-activators (Xu et al, 2004;Sakai et al, 2006) and co-repressors (Goodwin et al, 2000;Suzuki et al, 2003). NR5A2 controls cell type-specific programs through direct transcriptional regulation of discrete subsets of target genes (Chen et al, 2008;Holmstrom et al, 2011;Chong et al, 2012).…”

Transcriptional regulation by NR5A2 couples cell differentiation and inflammation in the pancreas

“…To assess whether Nr5a2 directly regulates the pre-inflammatory state, we took advantage of published pancreatic Nr5a2 ChIP-seq datasets (SRR389293 and SRR389294) 6 . Interestingly, the promoters of 89% of the genes whose expression was up-regulated in Nr5a2 +/-mice contain putative Nr5a2 binding sites but only 7% exhibited binding of Nr5a2 within 2.5 Kb from the transcriptional start site (TSS), suggesting the participation of an indirect mechanism ( Figure 2A).…”

“…The current notion is that the control of inflammatory responses relies on transcriptional networks distinct from those involved in cell differentiation 2,3 . The orphan nuclear receptor NR5A2 (also known as LRH-1) 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][5][6][7][8] . In mice, Nr5a2 deletion leads to variable degrees of pancreatic hypoplasia depending on the timing of its inactivation 6,8 .…”

“…The orphan nuclear receptor NR5A2 (also known as LRH-1) 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][5][6][7][8] . In mice, Nr5a2 deletion leads to variable degrees of pancreatic hypoplasia depending on the timing of its inactivation 6,8 . By contrast, constitutive Nr5a2 heterozygosity allows normal pancreatic development but is associated with impaired regeneration upon induction of mild acute inflammation and sensitizes pancreatic epithelial cells to mutant KRas-driven preneoplastic lesions and pancreatic ductal adenocarcinoma (PDAC) 9 .…”