FoxA2, Nkx2.2, and PDX-1 regulate islet β-cell-specific mafA expression through conserved sequences located between base pairs-8118 and-7750 upstream from the transcription start site

被引:102
作者
Raum, Jeffrey C.
Gerrish, Kevin
Artner, Isabella
Henderson, Eva
Guo, Min
Sussel, Lori
Schisler, Jonathan C.
Newgard, Christopher B.
Stein, Roland
机构
[1] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA
[2] NIEHS, Natl Ctr Toxicogenom, Res Triangle Pk, NC 27709 USA
[3] Univ Colorado, Hlth Sci Ctr, Dept Biochem & Mol Genet, Denver, CO 80045 USA
[4] Duke Univ, Ctr Med, Sarah W Stedman Nutr & Metab Ctr, Durham, NC 27704 USA
[5] Duke Univ, Ctr Med, Dept Pharmacol, Durham, NC 27704 USA
[6] Duke Univ, Ctr Med, Dept Canc Biol, Durham, NC 27704 USA
[7] Duke Univ, Ctr Med, Dept Med, Durham, NC 27704 USA
[8] Duke Univ, Ctr Med, Dept Biochem, Durham, NC 27704 USA
关键词
D O I
10.1128/MCB.00249-06
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The MafA transcription factor is both critical to islet beta-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 [3 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 by -8118 and -7750 (similar to 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 beta-cell-specific activity in cell-line-based reporter assays. Important regulators of beta-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 beta-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 beta-cell-type-specific mafA transcription is principally controlled by region 3-acting transcription factors that are essential in the formation of functional beta-cells.
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收藏
页码:5735 / 5743
页数:9
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