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

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 pancre...

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Autores principales: Fazio, Elena N., Young, Claire C., Toma, Jelena, Levy, Michael, Berger, Kurt R., Johnson, Charis L., Mehmood, Rashid, Swan, Patrick, Chu, Alphonse, Cregan, Sean P., Dilworth, F. Jeffrey, Howlett, Christopher J., Pin, Christopher L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576899/
https://www.ncbi.nlm.nih.gov/pubmed/28701342
http://dx.doi.org/10.1091/mbc.E17-04-0254
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author Fazio, Elena N.
Young, Claire C.
Toma, Jelena
Levy, Michael
Berger, Kurt R.
Johnson, Charis L.
Mehmood, Rashid
Swan, Patrick
Chu, Alphonse
Cregan, Sean P.
Dilworth, F. Jeffrey
Howlett, Christopher J.
Pin, Christopher L.
author_facet Fazio, Elena N.
Young, Claire C.
Toma, Jelena
Levy, Michael
Berger, Kurt R.
Johnson, Charis L.
Mehmood, Rashid
Swan, Patrick
Chu, Alphonse
Cregan, Sean P.
Dilworth, F. Jeffrey
Howlett, Christopher J.
Pin, Christopher L.
author_sort Fazio, Elena N.
collection PubMed
description 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.
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spelling pubmed-55768992017-11-16 Activating transcription factor 3 promotes loss of the acinar cell phenotype in response to cerulein-induced pancreatitis in mice Fazio, Elena N. Young, Claire C. Toma, Jelena Levy, Michael Berger, Kurt R. Johnson, Charis L. Mehmood, Rashid Swan, Patrick Chu, Alphonse Cregan, Sean P. Dilworth, F. Jeffrey Howlett, Christopher J. Pin, Christopher L. Mol Biol Cell Articles 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. The American Society for Cell Biology 2017-09-01 /pmc/articles/PMC5576899/ /pubmed/28701342 http://dx.doi.org/10.1091/mbc.E17-04-0254 Text en © 2017 Fazio et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Fazio, Elena N.
Young, Claire C.
Toma, Jelena
Levy, Michael
Berger, Kurt R.
Johnson, Charis L.
Mehmood, Rashid
Swan, Patrick
Chu, Alphonse
Cregan, Sean P.
Dilworth, F. Jeffrey
Howlett, Christopher J.
Pin, Christopher L.
Activating transcription factor 3 promotes loss of the acinar cell phenotype in response to cerulein-induced pancreatitis in mice
title Activating transcription factor 3 promotes loss of the acinar cell phenotype in response to cerulein-induced pancreatitis in mice
title_full Activating transcription factor 3 promotes loss of the acinar cell phenotype in response to cerulein-induced pancreatitis in mice
title_fullStr Activating transcription factor 3 promotes loss of the acinar cell phenotype in response to cerulein-induced pancreatitis in mice
title_full_unstemmed Activating transcription factor 3 promotes loss of the acinar cell phenotype in response to cerulein-induced pancreatitis in mice
title_short Activating transcription factor 3 promotes loss of the acinar cell phenotype in response to cerulein-induced pancreatitis in mice
title_sort activating transcription factor 3 promotes loss of the acinar cell phenotype in response to cerulein-induced pancreatitis in mice
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576899/
https://www.ncbi.nlm.nih.gov/pubmed/28701342
http://dx.doi.org/10.1091/mbc.E17-04-0254
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