Hnf1α (MODY3) regulates β-cell-enriched MafA transcription factor expression.

Hunter CS, Maestro MA, Raum JC, Guo M, Thompson FH, Ferrer J, Stein R
Mol Endocrinol. 2011 25 (2): 339-47

PMID: 21193557 · PMCID: PMC3386541 · DOI:10.1210/me.2010-0362

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.

MeSH Terms (15)

Animals Animals, Genetically Modified Blotting, Western Chromatin Immunoprecipitation Diabetes Mellitus, Type 2 DNA-Binding Proteins Electrophoretic Mobility Shift Assay Gene Expression Hepatocyte Nuclear Factor 1-alpha Humans Insulin-Secreting Cells Maf Transcription Factors, Large Mice Promoter Regions, Genetic Regulatory Sequences, Nucleic Acid

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