Abstract
Acinar-to-ductal metaplasia (ADM) occurring in cerulein-mediated pancreatitis or in oncogenic Kras-driven pancreatic cancer development is accompanied by extensive changes in the transcriptional program. In this process, acinar cells shut down the expression of acinar specific differentiation genes and re-express genes usually found in embryonic pancreatic progenitor cells. Previous studies have demonstrated that a loss of acinar-specific transcription factors sensitizes the cells towards oncogenic transformation, ultimately resulting in cancer development. However, the mechanism behind the transcriptional silencing of acinar cell fate genes in ADM and pancreatic cancer is largely unknown. Here, we analyzed whether elevated levels of the polycomb repressor complex 1 (PRC1) components Bmi1 and Ring1b and their catalyzed histone modification H2AK119ub in ADMs and tumor cells, are responsible for the mediation of acinar gene silencing. Therefore, we performed chromatin-immunoprecipitation in in vitro generated ADMs and isolated murine tumor cells against the repressive histone modifications H3K27me3 and H2AK119ub. We established that the acinar transcription factor complex Ptf1-L is epigenetically silenced in ADMs as well as in pancreatic tumor cells. For the first time, this work presents a possible mechanism of acinar gene silencing, which is an important prerequisite in the initiation and maintenance of a dedifferentiated cell state in ADMs and tumor cells.
Highlights
The exocrine compartment of the pancreas mainly consists of acinar cells producing digestive enzymes
Pancreatitis-driven organ disruption is accompanied by acinar-to-ductal metaplasia (ADM) where acinar cells lose their differentiated phenotype [3]
The expression of the histone modifying polycomb repressor complex 1 (PRC1) components Bmi1 and Ring1b and the level of the histone modification H2AK119ub were analyzed at two different points in time following cerulein-induced pancreatitis
Summary
The exocrine compartment of the pancreas mainly consists of acinar cells producing digestive enzymes. The activation of oncogenic Kras at physiological levels in adult www.impactjournals.com/oncotarget mice demonstrates, that Kras recapitulates its full oncogenic potential only in pancreatitis-driven ADM cells [2]. Within this process, ADM cells shut down the expression of acinar specific differentiation genes and acquire duct- and progenitor-like cell features [3]. Acinar cell fate is mainly controlled by the pancreas specific transcription factor-1 (PTF1), containing the DNA-binding subunit Ptf1a and either Rbpj (recombining binding protein suppressor of hairless) in pancreas progenitor cells or Rbpjl (Rbpj-like) in differentiated acinar cells [4]. A repression of acinar specific differentiation genes is an essential step in ADM and cancer progression and might be initiated by epigenetic changes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
