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Theranostics 2018; 8(12):3408-3415. doi:10.7150/thno.25156 This issue Cite

Research Paper

Circular RNA-ZNF609 regulates retinal neurodegeneration by acting as miR-615 sponge

Jia-Jian Wang^1*, Chang Liu^2*, Kun Shan^1,3*, Bai-Hui Liu⁴, Xiu-Miao Li², Shu-Jie Zhang^1,3, Rong-Mei Zhou¹, Rui Dong⁴, Biao Yan^1,3✉, Xing-Huai Sun^3,5,6✉

1. Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China
2. The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
3. NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, and Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai, China
4. Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
5. Department of Ophthalmology & Visual Science, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China
6. State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China
*These authors contributed equally to this work.

✉ Corresponding authors: Biao Yan, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, 200031, China. Tel:+862164377134; Fax: +862164377134; E-mail: yanbiao1982com or Xing-Huai Sun, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, 200031, China. E-mail: xhsunedu.cn More

Abstract

Glaucoma is a major cause of visual impairment characterized by progressive retinal neurodegeneration. Circular RNAs are a class of endogenous noncoding RNAs that regulate gene expression in eukaryotes. In this study, we investigated the role of cZNF609 in retinal neurodegeneration induced by glaucoma.

Methods: qRT-PCR and Sanger sequencing were conducted to detect cZNF609 expression pattern during retinal neurodegeneration. Immunofluorescence staining was conducted to detect the effect of cZNF609 silencing on retinal neurodegeneration in vivo. MTT assay, Ki67 staining, and PI staining were conducted to detect the effect of cZNF609 silencing on retinal glial cells and RGC function in vitro. Bioinformatics analysis, RNA pull-down assays, and in vitro studies were conducted to reveal the mechanism of cZNF609-mediated retinal neurodegeneration.

Results: cZNF609 expression was significantly up-regulated during retinal neurodegeneration. cZNF609 silencing reduced retinal reactive gliosis and glial cell activation, and facilitated RGC survival in vivo. cZNF609 silencing directly regulated Müller cell function but indirectly regulated RGC function in vitro. cZNF609 acted as an endogenous miR-615 sponge to sequester and inhibit miR-615 activity, which led to increased METRN. METRN overexpression could partially rescue cZNF609 silencing-mediated inhibitory effects on retinal glial cell proliferation.

Conclusion: Intervention of cZNF609 expression is a promising therapeutic strategy for retinal neurodegeneration.

Keywords: circular RNA, microRNA sponge, glaucoma, retinal neurodegeneration

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