title: Hnf1α (MODY3) regulates β-cell-enriched MafA transcription factor expression.
abstract: The expression pattern of genes important for pancreatic islet cell function requires the actions of cell-enriched transcription factors. Musculoaponeurotic fibrosarcoma homolog A (MafA) is a β-cell-specific transcriptional activator critical to adult islet β-cell function, with MafA mutant mice manifesting symptoms associated with human type 2 diabetes. Here, we describe that MafA expression is controlled by hepatocyte nuclear factor 1-α (Hnf1α), the transcription factor gene mutated in the most common monoallelic form of maturity onset diabetes of the young. There are six conserved sequence domains in the 5'-flanking MafA promoter, of which one, region 3 (R3) [base pair (bp) -8118/-7750] is principally involved in controlling the unique developmental and adult islet β-cell-specific expression pattern. Chromatin immunoprecipitation analysis demonstrated that Hnf1α bound specifically within R3. Furthermore, in vitro DNA-binding experiments localized an Hnf1α regulatory element between bp -7822 and -7793, an area previously associated with stimulation by the islet developmental regulator, Islet1. However, site-directed mutational studies showed that Hnf1α was essential to R3-driven reporter activation through bp -7816/-7811. Significantly, MafA levels were dramatically reduced in the insulin(+) cell population remaining in embryonic and adult Hnf1α(-/-) pancreata. Our results demonstrate that Hnf1α regulates MafA in β-cells and suggests that compromised MafA expression contributes to β-cell dysfunction in maturity onset diabetes of the young.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Chad S
authors.initials: CS
authors.lastname: Hunter
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Maestro
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Raum
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.forename: Frederick H
authors.initials: FH
authors.lastname: Thompson
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
authors.forename: Roland
authors.initials: R
authors.lastname: Stein
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051473:Maf Transcription Factors, Large / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C485159:MAFA protein, human; D051473:Maf Transcription Factors, Large