title: Polycomb repressor complex 1 promotes gene silencing through H2AK119 mono-ubiquitination in acinar-to-ductal metaplasia and pancreatic cancer cells.
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.
authors.affiliation: Department of Surgery, Technische Universität München, Munich, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Benitz
authors.affiliation: Department of Surgery, Technische Universität München, Munich, Germany.|Institute of Pathology, Heinrich-Heine University, Duesseldorf, Germany.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Regel
authors.affiliation: Department of Surgery, Technische Universität München, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Reinhard
authors.affiliation: Department of Surgery, Technische Universität München, Munich, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Popp
authors.affiliation: Department of Surgery, Technische Universität München, Munich, Germany.
authors.forename: Isabell
authors.initials: I
authors.lastname: Schäffer
authors.affiliation: Department of Surgery, Technische Universität München, Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Raulefs
authors.affiliation: Department of Surgery, Technische Universität München, Munich, Germany.
authors.forename: Bo
authors.initials: B
authors.lastname: Kong
authors.affiliation: Institute of Pathology, Heinrich-Heine University, Duesseldorf, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.affiliation: Department of Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Michalski
authors.affiliation: Department of Surgery, Technische Universität München, Munich, Germany.|The Royal Liverpool and Broadgreen University Hospitals, Liverpool, United Kingdom.|Department of Surgery, Heinrich-Heine University, Duesseldorf, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeff
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D054337:Cell Dedifferentiation / Q000235:genetics; D045744:Cell Line, Tumor; D020868:Gene Silencing; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D008679:Metaplasia / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063150:Polycomb Repressive Complex 1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D006657:Histones; D014157:Transcription Factors; C062602:transcription factor PTF1; D063150:Polycomb Repressive Complex 1
keywords: differentiation gene silencing; histone mono-ubiquitination; pancreatic cancer; polycomb repressor complex