Abstract
This work provides a comprehensive CpG methylation landscape of the different layers of the human eye that unveils the gene networks associated with their biological functions and how these are disrupted in common visual disorders. Herein, we firstly determined the role of CpG methylation in the regulation of ocular tissue-specification and described hypermethylation of retinal transcription factors (i.e., PAX6, RAX, SIX6) in a tissue-dependent manner. Second, we have characterized the DNA methylome of visual disorders linked to internal and external environmental factors. Main conclusions allow certifying that crucial pathways related to Wnt-MAPK signaling pathways or neuroinflammation are epigenetically controlled in the fibrotic disorders involved in retinal detachment, but results also reinforced the contribution of neurovascularization (ETS1, HES5, PRDM16) in diabetic retinopathy. Finally, we had studied the methylome in the most frequent intraocular tumors in adults and children (uveal melanoma and retinoblastoma, respectively). We observed that hypermethylation of tumor suppressor genes is a frequent event in ocular tumors, but also unmethylation is associated with tumorogenesis. Interestingly, unmethylation of the proto-oncogen RAB31 was a predictor of metastasis risk in uveal melanoma. Loss of methylation of the oncogenic mir-17-92 cluster was detected in primary tissues but also in blood from patients.
Highlights
Charles Darwin wrote in “The Origin of Species” that the human eye was an organ of extreme perfection that pushed to the limit its theory about natural selection
In this study we assessed the epigenetic characterization of visual disorders from a broader perspective, investigating the involvement of genome-wide CpG methylation in ocular diseases associated with environmental factors, inflammation and aging, and in ocular tumors
The substantial involvement of CpG methylation in tissue commitment was reflected by the clear segregation of the ocular layers in an unsupervised cluster exclusively using the methylation signals of the CpGs contained in the arrays (Fig. 1A)
Summary
Charles Darwin wrote in “The Origin of Species” that the human eye was an organ of extreme perfection that pushed to the limit its theory about natural selection. Aging-related eye diseases have become a priority problem in public health services due to their increasing prevalence in the general population and the seriousness of their impact on the quality of life of patients For this reason, in recent years increased attention has been paid to the molecular biology of ocular diseases, especially the genetic basis of these disorders[9,10]. Characterizing the normal epigenetic patterns that govern the maintenance of tissue-specificity of the adult mature eye is as important as profiling alterations in pathologies Considering both approaches (healthy versus pathological), we generated the largest CpG methylation map of embryonic and mature eye layers and their associated ocular diseases created so far. These data could be integrated to provide a comprehensive understanding of the epigenetic, genetic and environmental factors underlying visual disorders
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