The essential role of N6-methyladenosine RNA methylation in complex eye diseases

Abstract

There are many complex eye diseases which are the leading causes of blindness, however, the pathogenesis of the complex eye diseases is not fully understood, especially the underlying molecular mechanisms of N6-methyladenosine (m6A) RNA methylation in the eye diseases have not been extensive clarified. Our review summarizes the latest advances in the studies of m6A modification in the pathogenesis of the complex eye diseases, including cornea disease, cataract, diabetic retinopathy, age-related macular degeneration, proliferative vitreoretinopathy, Graves' disease, uveal melanoma, retinoblastoma, and traumatic optic neuropathy. We further discuss the possibility of developing m6A modification signatures as biomarkers for the diagnosis of the eye diseases, as well as potential therapeutic approaches.

Keywords: Degeneration; Eye diseases; Fibrosis; Inflammation; Tumor; m6A RNA methylation.

Figure 1

The relevance of m6A modification to ocular diseases. The diagram depicts that m6A modification contributes to numerous ocular diseases including inflammatory, angiogenetic, age, fibrotic, traumatic, metabolic, and tumorigenic eye diseases.

Figure 2

The expression of WTAP, FTO, and YTHDF3 in surgically excised human PDR membranes by immunofluorescent staining. Red indicates positive staining for WTAP, FTO, and YTHDF3. The cell nuclei are stained blue (DAPI). The immunofluorescent reactivities of WTAP, FTO, and YTHDF3 are considerably higher. Original magnification 200 × . PDR membranes (n = 3) (Unpublished data).

Figure 3

The contribution of epigenetic factors to the pathogenesis of AMD. The input of environmental factors may alter the epigenetic fingerprint, the Alterations in gene expression depend on the interaction of genetic (single nucleotide polymorphisms), epigenetic and environmental factors and thus the pathogenesis of AMD is regulated by multiple factors.

Figure 4

Expression of m6A writers (METTL3, METTL14, and WTAP), erasers (FTO and ALKBH5), and readers (YTHDF3) in human PVR membranes (from surgical excision). Red chromogen staining indicates the immunoreactivity of m6A modification factors, and blue indicates the nuclear contrast staining. magnification 200 × . PVR membranes (n = 3) (Unpublished data).

Figure 5

Effects of TGF-β on the mRNA expression of m6A methylases METTL3 in RPE cells (ARPE-19). ARPE-19 cells were treated with TGF-β2 (20 ng/ml, MedChemexpress, New Jersey, USA) for 24 h, and total RNA was isolated to analyze the expression of the genes by real-time PCR. The expression of METTL3 was significantly inhibited by adding TGF-β compared with control (t-test, ∗∗P < 0.01) (Unpublished data).

Figure 6

The prospective role of m6A modification in the pathogenesis of PVR. Retinal trauma induces the synthesis and secretion of TGF-β. TGF-β promotes the pathogenesis of PVR through the following pathways:1. activating snail through the Smad 2/3 pathways; 2. increasing FTO expression; 3. downregulating the expression of METTL3 (the negative regulator of EMT and fibrosis), which results in the repression of epithelial marker genes (E-cadherin and ZO-1) expression but enhances the mesenchymal gene (αSMA, FN, vimentin) expression and mesenchymal phenotype.