Toggle Main Menu Toggle Search

Open Access padlockePrints

Transcription Factor SOX9 Plays a Key Role in the Regulation of Visual Cycle Gene Expression in the Retinal Pigment Epithelium

Lookup NU author(s): Dr Ralf KistORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


Background: The visual cycle is an enzymatic cascade that regenerates the visual chromophore. Results: Visual cycle gene expression is regulated by SOX9 in combination with OTX2 or LHX2 and can be modulated by common microRNAs. Conclusion: A core transcriptional network involving SOX9 regulates visual cycle genes. Significance: Understanding visual cycle gene regulation may have implications for treating retinal degenerative diseases.The retinal pigment epithelium (RPE) performs specialized functions to support retinal photoreceptors, including regeneration of the visual chromophore. Enzymes and carrier proteins in the visual cycle function sequentially to regenerate and continuously supply 11-cis-retinal to retinal photoreceptor cells. However, it is unknown how the expression of the visual cycle genes is coordinated at the transcriptional level. Here, we show that the proximal upstream regions of six visual cycle genes contain chromatin-accessible sex-determining region Y box (SOX) binding sites, that SOX9 and LIM homeobox 2 (LHX2) are coexpressed in the nuclei of mature RPE cells, and that SOX9 acts synergistically with orthodenticle homeobox 2 (OTX2) to activate the RPE65 and retinaldehyde binding protein 1 (RLBP1) promoters and acts synergistically with LHX2 to activate the retinal G protein-coupled receptor (RGR) promoter. ChIP reveals that SOX9 and OTX2 bind to the promoter regions of RPE65, RLBP1, and RGR and that LHX2 binds to those of RPE65 and RGR in bovine RPE. ChIP with human fetal RPE cells shows that SOX9 and OTX2 also bind to the human RPE65, RLBP1, and RGR promoters. Conditional inactivation of Sox9 in mouse RPE results in reduced expression of several visual cycle genes, most dramatically Rpe65 and Rgr. Furthermore, bioinformatic analysis predicts that multiple common microRNAs (miRNAs) regulate visual cycle genes, and cotransfection of miRNA mimics with luciferase reporter constructs validated some of the predicted miRNAs. These results implicate SOX9 as a key regulator of visual cycle genes, reveal for the first time the functional role of LHX2 in the RPE, and suggest the possible regulation of visual cycle genes by common miRNAs.

Publication metadata

Author(s): Masuda T, Wahlin K, Wan J, Hu JF, Maruotti J, Yang X, Iacovelli J, Wolkow N, Kist R, Dunaief JL, Qian J, Zack DJ, Esumi N

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2014

Volume: 289

Issue: 18

Pages: 12908-12921

Print publication date: 02/05/2014

Online publication date: 14/03/2014

Date deposited: 10/06/2015

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology, Inc.


DOI: 10.1074/jbc.M114.556738


Altmetrics provided by Altmetric


Funder referenceFunder name
Wilmer Pooled Professor Research Fund
Foundation Fighting Blindness
Research to Prevent Blindness, Inc.
EY001765National Institutes of Health
EY016398National Institutes of Health
EY009769National Institutes of Health