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RESEARCH PRODUCT

DNA methylomes reveal biological networks involved in human eye development, functions and associated disorders

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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. The research leading to these results was supported by European Research Council Advanced Grant EPINORC, RecerCaixa Foundation, Federación Española de Enfermedades Raras (FEDER), Federación Española de Enfermedades Neuromusculares (ASEM), Fundación Isabel Gemio, COST CM1406, Instituto de Salud Carlos III (PI/00816) and Health and Sciences Departments of the Catalan Government (Generalitat de Catalunya). M.E. is an Institució Catalana de Recerca i Estudis Avançats (ICREA) Research Professor. We thank the staff of the Biobank Facility at the Bellvitge Biomedical Research Institute (IDIBELL), Spanish National Cancer Research Center (CNIO), Institute of Rare Diseases Research (BioNER-ISCIII), Vall d’Hebron Research Institute (VHIR) and Banc de Sang i Teixits (BST) of the Catalan Ministry of Health. We also thank Dr. Mercedes Hurtado (Department of Ophthalmology, University and Polytechnic Hospital La Fe) and Dr. Dolores Pinazo (Department of Ophthalmology, Dr. Peset University Hospital) for obtaining samples from glaucomatous patients. We thank the patients and their families. Sí