Dynamic changes in the epigenetic landscape are mandatory for acinar cell reprogramming and pancreatic carcinogenesis [ChIP-seq]

Pancreatic acinar cell reprogramming is described as a common hallmark in pancreatic regeneration and carcinogenesis, although the regulatory mechanisms are barely understood. To overcome limitations of cellular diversity posed by heterogeneous cell compositions and high stroma density in pathogenic tissue specimens, we have established a pure in vitro system mimicking the pancreatic carcinogenic sequence. With this model, we globally profiled for epigenetic and transcriptional alterations and demonstrate that regulatory key players and structural genes are extensively regulated by epigenetic mechanisms. A conditional knockout of the epigenetic repressor Ring1b showed that particularly the epigenetic silencing of acinar differentiation genes is a crucial step in acinar cell reprogramming and pancreatic cancer development. Moreover, a persistent epigenetic repression of these genes manifests tumor cell malignancy. Depletion or drug-dependent inhibition of Ring1b promoted tumor cell reprogramming towards a less aggressive phenotype offering new options for therapeutic intervention.