Impact of global DNA methylation on retinal gene expression in various stages of retinoblastoma: A clue for biomarkers

• Nawaf Almarzouki*

Abstract

Objectives: Retinoblastoma, the most prevalent intraocular cancer in children, originates from the eye's retina. Multi-omics studies reveal a complex molecular foundation for retinoblastoma, underscoring the crucial interconnected roles of epigenetic and gene expression processes in understanding pathological mechanisms, identifying biomarkers, and exploring potential therapeutic options. Methods: The DNA methylation array and gene expression datasets of retinoblastoma were searched in repositories. The relevant datasets were merged based on a common reference platform, and various regulatory patterns were constructed. Notably, canonical patterns containing hyper-DOWN and hypo-UP, localized at critical regions (such as 5ʹ UTR, 3ʹ UTR, TSS, shore, and shelves), were selected for mild, moderate, and severe retinoblastomas. Subsequently, common regulators across different disease states were identified, and their protein interactomes were generated and functionally enriched. Results: We analyzed global DNA methylation in 57 retinoblastoma and 20 normal retinal tissues. Additionally, we collected control, mild, moderate, and severe retinoblastoma gene expression datasets. Among 485,577 probes, 319 exhibited hypermethylation, and 2,846 showed hypomethylation in retinoblastoma. Significant (P < 0.05) UP- and DOWN-regulated genes for mild, moderate, and severe conditions were identified and mapped to hyper/hypomethylated probes. Notably, distinct regulation patterns (hyper-DOWN and hypo-UP) at critical regions were chosen for each disease state. Of these, 57 hyper-DOWN and 8 hypo-UP were common across all disease states, contributing to protein interaction networks with 318 extended proteins and 1,345 interactions essential in various neuronal and cancer-related pathways. Alternatively, a few distinct regulators were identified, providing clues for disease biomarkers. Conclusion: We found a strong association between hyper/hypomethylation and gene expression in retinoblastoma. These findings underscore the downstream regulatory role of DNA methylation, emphasizing stage-specific molecular mechanisms and offering insights into early biomarkers for the disease.

Keywords

Retinoblastoma, ocular tumor, ophthalmology , ocular genetics