Study of differentiation of acinair cells is important as dedifferentiated acini are the proposed cells of origin of pancreatic cancer but also have been shown to be a promising source for endocrine beta-cell generation in vitro. studies on pancreatic acinair cell differentiation have mainly been focused on the network of transcription factors that regulate their cell lineage commitment in the embryonic development and their stable differentiation as functional enzyme-secreting acini. Ther is however very little insight into the epigenetic regulation of this gene expression. Sirtuins, a peculiar class of Histone deacetylases that also target non-histoneproteins, have never been studied in this respect. Sirtuins are inhibited by nicotinamide, an end product of their catalytic reaction. We found that nicotinamide is a potent agent in maintaining acinar cell differentiation in an in vitro model of acinar cell metaplasia. We aim to study the expression and action of sirtuins in this culture system, and to identify the protein(s) that are targeted by the deacetylation reaction and that might thus be crucial for maintenance of acinar cells during embryonic development. In our approach, we will modulate sirtuin activity and expression, respectively by the use of an established pharmacological inhibitor and activator, a transgenetic mouse model with conditional sirt1 deficiency and lentiviral gene transfer. New insights will be gained into the epigenetic regulation of acinar cell differentiation.