A transcription factor regulatory circuit in differentiated pancreatic cells

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Abstract
Mutations in the human genes encoding hepatocyte nuclear factors (HNF) 1α, 1β, 4α, and IPF1(PDX1/IDX1/STF1) result in pancreatic β cell dysfunction and diabetes mellitus. In hepatocytes, hnf4α controls the transcription of hnf1α, suggesting that this same interaction may operate in β cells and thus account for the common diabetic phenotype. We show that, in pancreatic islet and exocrine cells, hnf4α expression unexpectedly depends on hnf1α. This effect is tissue-specific and mediated through direct occupation by hnf1α of an alternate promoter located 45.6 kb from the previously characterized hnf4α promoter. Hnf1α also exerts direct control of pancreatic-specific expression of hnf4γ and hnf3γ. Hnf1α dependence of hnf4α, hnf4γ, hnf3γ, 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 hnf1α is an essential component of a transcription factor circuit whose role may be to maintain differentiated functions of pancreatic cells.