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Comparative Analysis of Insulin Gene Promoters

Implications for Diabetes Research

From the School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, U.K

Address correspondence and reprint requests to Dr. K. Docherty, School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Aberdeen, AB25 2ZD, U.K. E-mail: k.docherty{at}abdn.ac.uk

Abbreviations: ChIP, chromatin immunoprecipitation; COUP-TFII, chicken ovalbumin upstream promoter–transcription factor II; CRE, cyclic AMP response element; ECR, evolutionary conserved region; HNF, hepatocyte nuclear factor; ILPR, insulin-linked polymorphic region; PDX-1, pancreatic duodenum homeobox-1

DNA sequences that regulate expression of the insulin gene are located within a region spanning 400 bp that flank the transcription start site. This region, the insulin promoter, contains a number of cis-acting elements that bind transcription factors, some of which are expressed only in the ß-cell and a few other endocrine or neural cell types, while others have a widespread tissue distribution. The sequencing of the genome of a number of species has allowed us to examine the manner in which the insulin promoter has evolved over a 450 million–year period. The major findings are that the A-box sites that bind PDX-1 are among the most highly conserved regulatory sequences, and that the conservation of the C1, E1, and CRE sequences emphasize the importance of MafA, E47/ß2, and cAMP-associated regulation. The review also reveals that of all the insulin gene promoters studied, the rodent insulin promoters are considerably dissimilar to the human, leading to the conclusion that extreme care should be taken when extrapolating rodent-based data on the insulin gene to humans.

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