GSE60250
Loss of Activating Transcription Factor 3 reveals a distinct gene expression program modulating cell organization during pancreatitis.
Pancreatitis is triggered by environmental or cellular stress and is the leading contributor to pancreatic ductal adenocarcinoma.  Altered gene expression in response to acinar cell stress determines the severity and duration of pancreatitis.  However, it is unclear what factors contribute to this phenomenon.  Here, we define a novel role for Activating Transcription Factor 3 (ATF3) during pancreatic injury. ATF3, a key mediator in the unfolded protein response, is robustly expressed in acinar cells during pancreatitis. Targeted deletion of Atf3 altered the molecular response to injury, with Atf3-/- acinar cells maintaining cell organization in response to cerulein, a well-established inducer of pancreatitis. Characterization of the mechanism using chromatin immunoprecipitation followed by Next Generation sequencing (ChIP-seq) identified 11,771 enrichment spots for ATF3, with known transcriptional start sites for >3,000 genes within 5 kb of ATF3 enrichment.  Gene ontology analysis revealed a significant representation of ATF3 enrichment to genes affecting cell organization, including Mist1, a molecule required for establishing acinar cell organization. We confirmed a direct interaction of ATF3 to the Mist1 promoter during pancreatitis, and showed that ATF3 is required for altered Mist1 expression in response to injury.  Finally, we demonstrate that ATF3 repression of Mist1 involves HDAC5. These findings suggest that ATF3 is a key transcriptional regulator during pancreatitis and promotes loss of the mature acinar cell phenotype in response to pancreatic injury. Overall design: Two samples were produced from male mice 4 hours after CIP initiation from intraparitoneal injections of cerulein, a ChIP sample using an ATF3 antibody and an IP control.