A transcription factor regulatory circuit in differentiated pancreatic cells.
Mutations in the human genes encoding hepatocyte nuclear factors (HNF) 1alpha, 1beta, 4alpha, and IPF1(PDX1/IDX1/STF1) result in pancreatic beta cell dysfunction and diabetes mellitus. In hepatocytes, hnf4alpha controls the transcription of hnf1alpha, 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, hnf4alpha expression unexpectedly depends on hnf1alpha. This effect is tissue-specific and mediated through direct occupation by hnf1alpha of an alternate promoter located 45.6 kb from the previously characterized hnf4alpha promoter. Hnf1alpha also exerts direct control of pancreatic-specific expression of hnf4gamma and hnf3gamma. Hnf1alpha dependence of hnf4alpha, hnf4gamma, hnf3gamma, 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 hnf1alpha is an essential component of a transcription factor circuit whose role may be to maintain differentiated functions of pancreatic cells.
Boj
S F
SF
Endocrinology and Hormonal Biochemistry Units, Hospital Clinic Universitari, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Villarroel 170, 08036 Barcelona, Spain.
Parrizas
M
M
Maestro
M A
MA
Ferrer
J
J
D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002454:Cell Differentiation; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D018398:Homeodomain Proteins; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins; D010179:Pancreas / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D014018:Tissue Distribution; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; C496592:HNF4A protein, human; C496597:HNF4G protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; C496593:Hnf4a protein, mouse; C496598:Hnf4g protein, mouse; D018398:Homeodomain Proteins; C403128:MLX protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; C501970:Tcfl4 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D004247:DNA