The pancreatic islet β-cell-enriched transcription factor Pdx-1 regulates Slc30a8 gene transcription through an intronic enhancer.

Pound LD, Hang Y, Sarkar SA, Wang Y, Milam LA, Oeser JK, Printz RL, Lee CE, Stein R, Hutton JC, O'Brien RM
Biochem J. 2011 433 (1): 95-105

PMID: 20942803 · PMCID: PMC4130494 · DOI:10.1042/BJ20101488

The SLC30A8 gene encodes the zinc transporter ZnT-8, which provides zinc for insulin-hexamer formation. Genome-wide association studies have shown that a polymorphic variant in SLC30A8 is associated with altered susceptibility to Type 2 diabetes and we recently reported that glucose-stimulated insulin secretion is decreased in islets isolated from Slc30a8-knockout mice. The present study examines the molecular basis for the islet-specific expression of Slc30a8. VISTA analyses identified two conserved regions in Slc30a8 introns 2 and 3, designated enhancers A and B respectively. Transfection experiments demonstrated that enhancer B confers elevated fusion gene expression in both βTC-3 cells and αTC-6 cells. In contrast, enhancer A confers elevated fusion gene expression selectively in βTC-3 and not αTC-6 cells. These data suggest that enhancer A is an islet β-cell-specific enhancer and that the mechanisms controlling Slc30a8 expression in α- and β-cells are overlapping, but distinct. Gel retardation and ChIP (chromatin immunoprecipitation) assays revealed that the islet-enriched transcription factor Pdx-1 binds enhancer A in vitro and in situ respectively. Mutation of two Pdx-1-binding sites in enhancer A markedly reduces fusion gene expression suggesting that this factor contributes to Slc30a8 expression in β-cells, a conclusion consistent with developmental studies showing that restriction of Pdx-1 to pancreatic islet β-cells correlates with the induction of Slc30a8 gene expression and ZnT-8 protein expression in vivo.

MeSH Terms (14)

Animals Binding Sites Cation Transport Proteins Enhancer Elements, Genetic Gene Expression Regulation Homeodomain Proteins Introns Islets of Langerhans Mice Tissue Distribution Trans-Activators Transcription, Genetic Transcription Factors Zinc Transporter 8

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