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FoxA2, Nkx2.2, and PDX-1 Regulate Islet ß-Cell-Specific mafA Expression through Conserved Sequences Located between Base Pairs –8118 and –7750 Upstream from the Transcription Start Site

Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232,¹ National Center for Toxicogenomics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709,² Department of Biochemistry and Molecular Genetics, University of Colorado Health Science Center, Denver, Colorado 80045,³ Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology and Cancer Biology, Medicine, and Biochemistry, Duke University Medical Center, Durham, North Carolina 27704⁴

Received 9 February 2006/ Returned for modification 29 March 2006/ Accepted 2 May 2006

The MafA transcription factor is both critical to islet ß-cell function and has a unique pancreatic cell-type-specific expression pattern. To localize the potential transcriptional regulatory region(s) involved in directing expression to the ß cell, areas of identity within the 5' flanking region of the mouse, human, and rat mafA genes were found between nucleotides –9389 and –9194, –8426 and –8293, –8118 and –7750, –6622 and –6441, –6217 and –6031, and –250 and +56 relative to the transcription start site. The identity between species was greater than 75%, with the highest found between bp –8118 and –7750 (94%, termed region 3). Region 3 was the only upstream mammalian conserved region found in chicken mafA (88% identity). In addition, region 3 uniquely displayed ß-cell-specific activity in cell-line-based reporter assays. Important regulators of ß-cell formation and function, PDX-1, FoxA2, and Nkx2.2, were shown to specifically bind to region 3 in vivo using the chromatin immunoprecipitation assay. Mutational and functional analyses demonstrated that FoxA2 (bp –7943 to –7910), Nkx2.2 (bp –7771 to –7746), and PDX-1 (bp –8087 to –8063) mediated region 3 activation. Consistent with a role in transcription, small interfering RNA-mediated knockdown of PDX-1 led to decreased mafA mRNA production in INS-1-derived ß-cell lines (832/13 and 832/3), while MafA expression was undetected in the pancreatic epithelium of Nkx2.2 null animals. These results suggest that ß-cell-type-specific mafA transcription is principally controlled by region 3-acting transcription factors that are essential in the formation of functional ß cells.

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