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Krüppel-like Factor 15, a Zinc-Finger Transcriptional Regulator, Represses the Rhodopsin and Interphotoreceptor Retinoid-Binding Protein Promoters

¹From the Guerrieri Center for Genetic Engineering and Molecular Ophthalmology at the Wilmer Eye Institute; the ²Departments of Ophthalmology, ⁵Neuroscience, and ⁶Molecular Biology and Genetics; and the ⁷Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and the ⁴Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. ³Current affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California.

PURPOSE. To identify novel transcriptional regulators of rhodopsin expression as a model for understanding photoreceptor-specific gene regulation.

METHODS. A bovine retinal cDNA library was screened in a yeast one-hybrid assay, with a 29-bp bovine rhodopsin promoter fragment as bait. Expression studies used RT-PCR and ß-galactosidase (LacZ) histochemistry of retinas from transgenic mice heterozygous for a targeted LacZ replacement of KLF15. Promoter transactivation assays measured luciferase expression in HEK293 cells transiently transfected with bovine rhodopsin or IRBP promoter–reporter constructs and expression constructs containing cDNAs for full or truncated KLF15, Crx (cone rod homeobox), and/or Nrl (neural retina leucine zipper). Data were analyzed with general linear models.

RESULTS. The zinc-finger transcription factor KLF15 was identified as a rhodopsin-promoter–binding protein in a yeast one-hybrid screen. Expression was detected by RT-PCR in multiple tissues, including the retina, where KLF15-LacZ was observed in the inner nuclear layer, ganglion cell layer, and pigmented epithelial cells, but not in photoreceptors. KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. Repressor activity required both a 198-amino-acid element in the N-terminal domain and the C-terminal zinc finger DNA-binding domains.

CONCLUSIONS. The zinc finger containing transcription factor KLF15 is a transcriptional repressor of the rhodopsin and IRBP promoters in vitro and, in the retina, is a possible participant in repression of photoreceptor-specific gene expression in nonphotoreceptor cells.

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