title: Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function.
abstract: Mutations in the genes encoding hepatocyte nuclear factor 4alpha (HNF-4alpha) and HNF-1alpha impair insulin secretion and cause maturity onset diabetes of the young (MODY). HNF-4alpha is known to be an essential positive regulator of HNF-1alpha. More recent data demonstrates that HNF-4alpha expression is dependent on HNF-1alpha in mouse pancreatic islets and exocrine cells. This effect is mediated by binding of HNF-1alpha to a tissue-specific promoter (P2) located 45.6 kb upstream from the previously characterized Hnf4alpha promoter (P1). Here we report that the expression of HNF-4alpha in human islets and exocrine cells is primarily mediated by the P2 promoter. Furthermore, we describe a G --> A mutation in a conserved nucleotide position of the HNF-1alpha binding site of the P2 promoter, which cosegregates with MODY. The mutation results in decreased affinity for HNF-1alpha, and consequently in reduced HNF-1alpha-dependent activation. These findings provide genetic evidence that HNF-1alpha serves as an upstream regulator of HNF-4alpha and interacts directly with the P2 promoter in human pancreatic cells. Furthermore, they indicate that this regulation is essential to maintain normal pancreatic function.
authors.affiliation: Steno Diabetes Center and Hagedorn Research Institute, Gentofte, Denmark. toha@dadlnet.dk
authors.forename: Sara K
authors.initials: SK
authors.lastname: Hansen
authors.forename: Marcelina
authors.initials: M
authors.lastname: Párrizas
authors.forename: Maria L
authors.initials: ML
authors.lastname: Jensen
authors.forename: Stepanka
authors.initials: S
authors.lastname: Pruhova
authors.forename: Jakob
authors.initials: J
authors.lastname: Ek
authors.forename: Sylvia F
authors.initials: SF
authors.lastname: Boj
authors.forename: Anders
authors.initials: A
authors.lastname: Johansen
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Maestro
authors.forename: Francisca
authors.initials: F
authors.lastname: Rivera
authors.forename: Hans
authors.initials: H
authors.lastname: Eiberg
authors.forename: Michal
authors.initials: M
authors.lastname: Andel
authors.forename: Jan
authors.initials: J
authors.lastname: Lebl
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D017930:Genes, Reporter; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D007223:Infant; D007515:Islets of Langerhans / Q000502:physiology*; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: 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; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; C403128:MLX protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011965:Receptors, Glucocorticoid; C501970:Tcfl4 protein, mouse; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta