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Conserved Transcriptional Regulatory Domains of the pdx-1 Gene

Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37215

Address all correspondence and requests for reprints to: Roland Stein, Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 723 Light Hall, Nashville, Tennessee 37215. E-mail: roland.stein{at}vanderbilt.edu.

The pancreas and duodenum homeobox protein 1 (PDX-1) homeodomain-containing transcription factor affects both pancreatic endocrine cell development and adult islet ß-cell function. Cell-type-specific expression is controlled by sequences 5' flanking the pdx-1 gene transcription start site. One principal control region is located roughly between -2800 and -1600 bp and spans three conserved, distinct, and functionally important subdomains, termed areas I, II, and III. In this study, we found that an upstream control region in the rat pdx-1 gene located between -6200 and -5670 bp is also present in the mouse, chicken, and human genes. This region is capable of independently directing pancreatic ß-cell-selective reporter gene expression and potentiating area I/II-driven activity. This newly recognized conserved subdomain has been termed area IV. The islet-enriched forkhead box A2 (FoxA2), NK2 homeobox 2.2 (Nkx2.2), and pancreas and duodenum homeobox protein 1 (PDX-1) transcription factors have been shown to activate area IV-driven reporter gene expression as well as bind to this region of the endogenous gene in ß-cells. Analysis of the histone H3 and H4 acetylation level also indicated that areas I–IV are within transcriptionally active chromatin in ß-cells. Our data suggests that pdx-1 transcription is also regulated by factors acting upon conserved area IV sequences.

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