EP300 Protects from Light-Induced Retinopathy in Zebrafish.

Reiko Kawase,Yuhei Nishimura,Masamitsu Shimazawa,Shota Sasagawa,Hiroshi Yamamoto,Soichiro Murakami,Koki Kawaguchi,Yoshifumi Ashikawa,Shinsaku Yamane,Toshio Tanaka,Mizuki Yuge,Hideaki Hara,Kazumi Moriyuki,Shiko Okabe,Kazuhiro Tsuruma

doi:10.3389/fphar.2016.00126

Abstract

Exposure of rhodopsin to bright white light can induce photoreceptor cell damage and degeneration. However, a comprehensive understanding of the mechanisms underlying light-induced retinopathy remains elusive. In this study, we performed comparative transcriptome analysis of three rodent models of light-induced retinopathy, and we identified 37 genes that are dysregulated in all three models. Gene ontology analysis revealed that this gene set is significantly associated with a cytokine signaling axis composed of signal transducer and activator of transcription 1 and 3 (STAT1/3), interleukin 6 signal transducer (IL6ST), and oncostatin M receptor (OSMR). Furthermore, the analysis suggested that the histone acetyltransferase EP300 may be a key upstream regulator of the STAT1/3–IL6ST/OSMR axis. To examine the role of EP300 directly, we developed a larval zebrafish model of light-induced retinopathy. Using this model, we demonstrated that pharmacological inhibition of EP300 significantly increased retinal cell apoptosis, decreased photoreceptor cell outer segments, and increased proliferation of putative Müller cells upon exposure to intense light. These results suggest that EP300 may protect photoreceptor cells from light-induced damage and that activation of EP300 may be a novel therapeutic approach for the treatment of retinal degenerative diseases.

Highlights

Retinal photoreceptor cells are uniquely adapted to function over a wide range of ambient light conditions
We demonstrated that (i) a signaling axis composed of signal transducer and activator of transcription 1 and 3 (STAT1/3), interleukin 6 signal transducer (IL6ST), and oncostatin M receptor (STAT1/3–IL6ST/OSMR), which is involved in the neuroprotective role of IL-6 (Jung et al, 2011), plays a key role in light-induced retinopathy, (ii) the histone acetyltransferase (HAT) EP300 is a key upstream regulator of the STAT1/3– IL6ST/OSMR axis, and (iii) EP300 plays a protective role in the larval zebrafish model of light-induced retinopathy, suggesting that EP300 may be a novel therapeutic target for retinal degenerative diseases
These results suggest that STAT1/3–IL6ST/OSMR may be a key signaling pathway in the pathophysiology of light-induced retinopathy

Summary

Introduction

Retinal photoreceptor cells are uniquely adapted to function over a wide range of ambient light conditions. In most species, prolonged exposure to intense visible light can lead to photoreceptor cell damage (reviewed in Wenzel et al, 2005; Organisciak and Vaughan, 2010; Chen et al, 2016). Light-induced retinal damage serves as a model to study human retinal degeneration arising from environmental insult, aging, and genetic disease. Animal models of light-induced retinopathy have been used successfully to develop therapeutic approaches for retinal degenerative diseases (Tsuruma et al, 2014; Shimazawa et al, 2015). While many of the light-induced retinopathy models share similar mechanisms, there are significant differences (reviewed in Organisciak and Vaughan, 2010).

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Conclusion