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

Mol Endocrinol. 2011 Feb;25(2):339-47. doi: 10.1210/me.2010-0362. Epub 2010 Dec 30.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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

Substances

  • DNA-Binding Proteins
  • HNF1A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • MAFA protein, human
  • Maf Transcription Factors, Large