# Dysregulated DNA Methylation in Abca4-/- Retinal Pigment Epithelium: Insights into Early Stage of Stargardt Disease

## TL;DR

This study explores early DNA methylation changes in a mouse model of Stargardt disease, suggesting these changes may contribute to retinal cell dysfunction and loss.

## Contribution

The study identifies early DNA methylation changes in Abca4-/- RPE and links them to potential regulators like MeCP2 and REST.

## Key findings

- Hypermethylation of gene regions linked to disease pathways was observed in Abca4-/- RPE.
- DNA methylation changes preceded transcriptional changes and disease phenotypes in the model.
- MeCP2 levels increased with age in Abca4-/- RPE, suggesting a role in disease progression.

## Abstract

Stargardt disease (STGD1), the most common inherited juvenile macular degeneration, is caused by biallelic mutations in the ABCA4 gene. Currently, there is no approved treatment. In this study, we investigated early-stage epigenomic changes in the retinal pigment epithelium (RPE) of Abca4-/- mice, a well-established model of STGD1. Reduced representation bisulfite sequencing (RRBS) revealed hypermethylation of gene regions associated with disease-related pathways, implicating methyl-CpG-binding protein 2 (MeCP2) and RE1-silencing transcription factor (REST) as potential regulators. Notably, DNA methylation of a subset of genes preceded their transcriptional change and disease phenotypes in Abca4-/- RPE. Together with the detected age-dependent increase in MeCP2 levels in Abca4-/- RPE, these findings suggest that early DNA methylation changes may contribute to RPE dysfunction and eventual cell loss in STGD1.