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: Chad S Hunter, Miguel Angel Maestro, Jeffrey C Raum, Min Guo, Frederick H Thompson 3rd, Jorge Ferrer, Roland Stein
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 25 Issue 2 Pg. 339-47 (Feb 2011) ISSN: 1944-9917 [Electronic] United States
• PMID: 21193557 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

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