Journal Article

<i>BEST1</i> expression in the retinal pigment epithelium is modulated by OTX family members

Noriko Esumi, Shu Kachi, Laszlo Hackler, Tomohiro Masuda, Zhiyong Yang, Peter A. Campochiaro and Donald J. Zack

in Human Molecular Genetics

Volume 18, issue 1, pages 128-141
Published in print January 2009 | ISSN: 0964-6906
Published online October 2008 | e-ISSN: 1460-2083 | DOI:
BEST1 expression in the retinal pigment epithelium is modulated by OTX family members

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A number of genes preferentially expressed in the retinal pigment epithelium (RPE) are associated with retinal degenerative disease. One of these, BEST1, encodes bestrophin-1, a protein that when mutated causes Best macular dystrophy. As a model for RPE gene regulation, we have been studying the mechanisms that control BEST1 expression, and recently demonstrated that members of the MITF–TFE family modulate BEST1 transcription. The human BEST1 upstream region from −154 to +38 bp is sufficient to direct expression in the RPE, and positive-regulatory elements exist between −154 and −104 bp. Here, we show that the −154 to −104 bp region is necessary for RPE expression in transgenic mice and contains a predicted OTX-binding site (Site 1). Since another non-canonical OTX site (Site 2) is located nearby, we tested the function of these sites using BEST1 promoter/luciferase constructs by in vivo electroporation and found that mutation of both sites reduces promoter activity. Three OTX family proteins – OTX1, OTX2 and CRX – bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity. Surprisingly, we found that human and bovine RPE expressed not only OTX2 but also CRX, the CRX genomic region in bovine RPE was hypersensitive to DNase I, consistent with active transcription, and that both OTX2 and CRX bound to the BEST1 proximal promoter in vivo. These results demonstrate for the first time CRX expression in the RPE, and suggest that OTX2 and CRX may act as positive modulators of the BEST1 promoter in the RPE.

Journal Article.  10562 words.  Illustrated.

Subjects: Genetics and Genomics

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