A transcription factor regulatory circuit in differentiated pancreatic cells

Mutations in the human genes encoding hepatocyte nuclear factors (HNF) 1 alpha, 1 beta, 4 alpha, and IPF1(PDX1/IDX1/STF1) result in pancreatic beta cell dysfunction and diabetes mellitus. In hepatocytes, hnf4 alpha controls the transcription of hnf1 alpha, suggesting that this same interaction may operate in beta cells and thus account for the common diabetic phenotype. We show that, in pancreatic islet and exocrine cells, hnf4 alpha expression unexpectedly depends on hnf1 alpha This effect is tissue-specific and mediated through direct occupation by hnf1 alpha a of an alternate promoter located 45.6 kb from the previously characterized hnf4 alpha promoter. Hnf1 alpha also exerts direct control of pancreatic-specific expression of hnf4 gamma and hnf3 gamma. Hnf1 alpha dependence of hnf4 alpha, hnf4 gamma, hnf3 gamma, and two previously characterized distal targets (glut2 and pklr) is established only after differentiated cells arise during pancreatic embryonic development. These studies define an unexpected hierarchical regulatory relationship between two genes involved in human monogenic diabetes in the cells, which are relevant to its pathophysiology. Furthermore, they indicate that hnf1 alpha is an essential component of a transcription factor circuit whose role may be to maintain differentiated functions of pancreatic cells.