title: A distant upstream promoter of the HNF-4alpha gene connects the transcription factors involved in maturity-onset diabetes of the young.
abstract: Maturity-onset diabetes of the young (MODY) is a monogenic, autosomal dominant subtype of early-onset diabetes mellitus due to defective insulin secretion by the pancreatic beta-cell in humans. Five different genes have been identified including those encoding the tissue-specific transcription factors expressed in pancreatic beta-cells, i.e. HNF-4alpha (MODY1), HNF-1alpha (MODY3), IPF-1 (also known as PDX-1, MODY4) and HNF-1beta (MODY5). Analyzing the transcription of the HNF-4alpha gene, we now identify an alternative promoter, P2, which is 46 kb 5' to the previously identified P1 promoter of the human gene. Based on RT-PCR this distant upstream P2 promoter represents the major transcription site in pancreatic beta-cells, but is also used in hepatic cells. Transfection assays with various deletions and mutants of the P2 promoter reveal functional binding sites for HNF-1alpha, HNF-1beta and IPF-1, the other transcription factors known to encode MODY genes. We demonstrate the significance of this alternative promoter in a large MODY family where a mutated IPF-1 binding site in the P2 promoter of the HNF-4alpha gene co-segregates with diabetes (LOD score 3.25). These data suggest a regulatory network of the four MODY transcription factors interconnected at the distant upstream P2 promoter of the HNF-4alpha gene.
authors.affiliation: Institut für Zellbiologie (Tumorforschung), Universitätsklinikum Essen, Hufelandstrasse 55, D-45122 Essen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Thomas
authors.forename: K
authors.initials: K
authors.lastname: Jaschkowitz
authors.forename: M
authors.initials: M
authors.lastname: Bulman
authors.forename: T M
authors.initials: TM
authors.lastname: Frayling
authors.forename: S M
authors.initials: SM
authors.lastname: Mitchell
authors.forename: S
authors.initials: S
authors.lastname: Roosen
authors.forename: A
authors.initials: A
authors.lastname: Lingott-Frieg
authors.forename: C J
authors.initials: CJ
authors.lastname: Tack
authors.forename: S
authors.initials: S
authors.lastname: Ellard
authors.forename: G U
authors.initials: GU
authors.lastname: Ryffel
authors.forename: A T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D051557:Hepatocyte Nuclear Factor 4; D018398:Homeodomain Proteins; D006801:Humans; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured / Q000502:physiology
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D017931:DNA Primers; D004268:DNA-Binding Proteins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D018398:Homeodomain Proteins; C403128:MLX protein, human; D010750:Phosphoproteins; C501970:Tcfl4 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein; D008156:Luciferases