Activating transcription factor 3 promotes loss of the acinar cell phenotype in response to cerulein-induced pancreatitis in mice

Author:

Fazio Elena N.123,Young Claire C.124,Toma Jelena124,Levy Michael1,Berger Kurt R.12,Johnson Charis L.12,Mehmood Rashid12,Swan Patrick45,Chu Alphonse6,Cregan Sean P.45,Dilworth F. Jeffrey7,Howlett Christopher J.7,Pin Christopher L.1234

Affiliation:

1. Children’s Health Research Institute, London, ON N6C 2V5, Canada

2. Department of Paediatrics, University of Western Ontario, London, ON N6A 3K7, Canada

3. Department of Oncology, University of Western Ontario, London, ON N6A 3K7, Canada

4. Department of Physiology and Pharmacology, University of Western Ontario, London, ON N6A 3K7, Canada

5. Robarts Research Institute, University of Western Ontario, London, ON N6A 5B7, Canada

6. Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada

7. Department of Pathology and Laboratory Medicine, University of Western Ontario, London, ON N6A 3K7, Canada

Abstract

Pancreatitis is a debilitating disease of the exocrine pancreas that, under chronic conditions, is a major susceptibility factor for pancreatic ductal adenocarcinoma (PDAC). Although down-regulation of genes that promote the mature acinar cell fate is required to reduce injury associated with pancreatitis, the factors that promote this repression are unknown. Activating transcription factor 3 (ATF3) is a key mediator of the unfolded protein response, a pathway rapidly activated during pancreatic insult. Using chromatin immunoprecipitation followed by next-generation sequencing, we show that ATF3 is bound to the transcriptional regulatory regions of >30% of differentially expressed genes during the initiation of pancreatitis. Of importance, ATF3-dependent regulation of these genes was observed only upon induction of pancreatitis, with pathways involved in inflammation, acinar cell differentiation, and cell junctions being specifically targeted. Characterizing expression of transcription factors that affect acinar cell differentiation suggested that acinar cells lacking ATF3 maintain a mature cell phenotype during pancreatitis, a finding supported by maintenance of junctional proteins and polarity markers. As a result, Atf3–/– pancreatic tissue displayed increased tissue damage and inflammatory cell infiltration at early time points during injury but, at later time points, showed reduced acinar-to–duct cell metaplasia. Thus our results reveal a critical role for ATF3 as a key regulator of the acinar cell transcriptional response during injury and may provide a link between chronic pancreatitis and PDAC.

Publisher

American Society for Cell Biology (ASCB)

Subject

Cell Biology,Molecular Biology

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