title: Silencing of the Fibroblast growth factor 21 gene is an underlying cause of acinar cell injury in mice lacking MIST1.
abstract: Fibroblast growth factor 21 (FGF21) is a key regulator of metabolism under conditions of stress such as starvation, obesity, and hypothermia. Rapid induction of FGF21 is also observed in experimental models of pancreatitis, and FGF21 reduces tissue damage observed in these models, suggesting a nonmetabolic function. Pancreatitis is a debilitating disease with significant morbidity that greatly increases the risk of pancreatic ductal adenocarcinoma. The goals of this study were to examine the regulation and function of FGF21 in acinar cell injury, specifically in a mouse model of pancreatic injury (Mist1(-/-)). Mist1(-/-) mice exhibit acinar cell disorganization, decreased acinar cell communication and exocytosis, and increased sensitivity to cerulein-induced pancreatitis (CIP). Examination of Fgf21 expression in Mist1(-/-) mice by qRT-PCR, Northern blot, and Western blot analyses showed a marked decrease in pancreatic Fgf21 expression before and after induction of CIP compared with C57Bl/6 mice. To determine whether the loss of FGF21 accounted for the Mist1(-/-) phenotypes, we generated Mist1(-/-) mice overexpressing human FGF21 from the ApoE promoter (Mist1(-/-)ApoE-FGF21). Reexpression of FGF21 partially mitigated pancreatic damage in Mist1(-/-) tissue based on reduced intrapancreatic enzyme activation, reduced expression of genes involved in fibrosis, and restored cell-cell junctions. Interestingly, alteration of Fgf21 expression in Mist1(-/-) tissue was not simply due to a loss of direct transcriptional regulation by MIST1. Chromatin immunopreciptation indicated that the loss of Fgf21 in the Mist1(-/-) pancreas is due, in part, to epigenetic silencing. Thus, our studies identify a new role for FGF21 in reducing acinar cell injury and uncover a novel mechanism for regulating Fgf21 gene expression.
authors.affiliation: Children's Health Research Institute, London, Ontario, Canada;
authors.forename: Charis L
authors.initials: CL
authors.lastname: Johnson
authors.forename: Rashid
authors.initials: R
authors.lastname: Mehmood
authors.forename: Scott W
authors.initials: SW
authors.lastname: Laing
authors.forename: Camilla V
authors.initials: CV
authors.lastname: Stepniak
authors.forename: Alexei
authors.initials: A
authors.lastname: Kharitonenkov
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Pin
mesh_terms: D061354:Acinar Cells / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002478:Cells, Cultured; D005346:Fibroblast Growth Factors / Q000235:genetics*; D020868:Gene Silencing / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D010195:Pancreatitis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005346:Fibroblast Growth Factors; C491312:Bhlha15 protein, mouse; C414620:fibroblast growth factor 21
keywords: MIST1; epigenetics; gene silencing; histone methylation; pancreatitis