The sodium/glucose cotransporter (SGLT1) is expressed primarily by small intestinal cells and transports the monosaccharides, glucose and galactose, across the apical membrane. As the exclusive transporter of luminal glucose and galactose, SGLT1's function is essential for adequate assimilation of a diet rich in dairy products and other processed sugars. Inherited mutations of the SGLT1 gene result in the autosomal recessive disorder, glucose/galactose malabsorption, that typically presents shortly after birth with severe life-threatening malabsorption. In humans expression of SGLT1, which is controlled primarily at the level of transcription, varies in a diurnal pattern. The investigator has carefully dissected the promoter-proximal element of the SGLT1 gene and determined the critical role that SP1 and HNF-1 play in driving basil expression in various cell lines. However, this region alone is not sufficient to establish consistent expression of the luciferase reported in the intestine of transgenic mouse lines. These data were interpreted to suggest that other distal regulatory elements must exist in order to drive intestine-specific expression of SGLT1. To begin identifying the critical locus control region of the SGLT1 gene, the investigator has cloned 40 kb of the 5-upstream region and its entire nucleotide sequence has been determined. He now proposes to test the hypothesis that expression of SGLT1 gene is controlled by a distal regulatory locus. This will be done by achieving two specific aims. The first is to identify the tissue-specific DNase1 hypersensitivity sites in the regions surrounding the SGLT1 gene. The second is to use both in vivo and in vitro models to assess the potential role of the DNA elements identified by DNase1 hypersensitivity assays to control SGLT1 expression. The regulatory control regions of the SGLT1 gene must contain various nuclear protein regulatory elements that control its transcriptional regulation in a unique tissue and temporal pattern of expression. The identification and further characterization of these cis elements will provide better insight into the molecular mechanism of enterocyte-specific cell fate and the various factors mediating its regulation.
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