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

Sam R. Holmstrom; Tye Deering; Galvin H. Swift; Frank J. Poelwijk; David J. Mangelsdorf; Steven A. Kliewer; Raymond J. MacDonald

doi:10.1101/gad.16860911

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

¹Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
²Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
³Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
⁴Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

↵5 These authors contributed equally to this work.

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.