A binary mechanism for the selective action of a pancreatic beta -cell transcriptional silencer.

The pancreatic elastase I gene (ELA1) is selectively transcribed to high levels in pancreatic acinar cells. Pancreatic specificity is imparted by a 100-base pair enhancer that activates transcription in beta-cells of the islets of Langerhans as well as in acinar cells. Adjacent to the enhancer is a silencer that renders transcription specific to acinar cells by selectively suppressing the inherent beta-cell activity of the enhancer. We show that the selective repression of beta-cell transcription is due neither to a beta-cell specific activity of the silencer nor to selective interference with beta-cell-specific transcriptional activators acting on the enhancer. Rather, the silencer is effective in both pancreatic endocrine and acinar cell types against all low and moderate strength enhancers and promoters tested. The silencer appears to act in a binary manner by reducing the probability that a promoter will be active without affecting the rate of transcription from active promoters. We propose that the ELA1 silencer is a weak off switch capable of inactivating enhancer/promoter combinations whose strength is below a threshold level but ineffective against stronger enhancer/promoters. The apparent cell-specific effects on the ELA1 enhancer appear due to the ability of the silencer to inactivate the weak beta-cell activity of the enhancer but not the stronger acinar cell activity.