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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.

We have analyzed the function of individual elements of the elastase I transcriptional enhancer in transgenic animals. This pancreas-specific enhancer comprises three functional elements, one of which (the B element) plays a dual role. Within the context of the enhancer, the B element contributes to appropriate acinar cell expression. However, when separated from the other enhancer components, the B element selectively directs transcription in islet cells of transgenic animals. This islet-specific activity is normally suppressed by an upstream repressor domain. The B element binds a novel islet-specific factor, and similar B-like elements are present in other pancreatic genes, both exocrine and endocrine specific. We suggest that a principal role of this transcriptional element and its associated factors is to activate many pancreatic genes as part of the program of pancreatic determination prior to the divergence of the acinar and islet cell lineages.

The 134-bp enhancer region of the pancreatic elastase I gene is sufficient to direct pancreatic acinar cell-specific transcription in transgenic mice and in transfected cells in culture. Ten-base-pair scanner mutations in three separate enhancer domains that inactivate enhancer function in transfected pancreatic cells in culture have no significant effect in transgenic mice. Because any pair of the three domains is sufficient to direct pancreas-specific expression in mice, no one domain is required for pancreas-specific transcription. Disruption of any two domains does inactivate the enhancer function in transgenic mice. Therefore, the elastase I enhancer domains essential for function in transfected cells in culture are not essential in animals but have a redundant function not apparent in transfected cells. This redundant function is not because of the particular acinar cell line used for transfections, the nature of the reporter gene, or the state of integration of the foreign test gene. We conclude that a trans-acting transcription factor or a modification of a factor(s) present in pancreatic cells of an animal is absent in pancreatic acinar cell lines.