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Updated: Apr 19, 2026
Immunohistochemical Detection of 5-Methylcytosine and 5-Hydroxymethylcytosine in Developing and Postmitotic Mouse Retina
Published on: August 29, 2018
DNA methylation and differential gene regulation in photoreceptor cell death
P Farinelli1, A Perera2, B Arango-Gonzalez3
11] Division of Ophthalmology, Department of Clinical Sciences, University of Lund, BMC-B11, Lund 22184, Sweden [2] Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen 72076, Germany.
Abstract:
Retinitis pigmentosa (RP) defines a group of inherited degenerative retinal diseases causing progressive loss of photoreceptors. To this day, RP is still untreatable and rational treatment development will require a thorough understanding of the underlying cell death mechanisms. Methylation of the DNA base cytosine by DNA methyltransferases (DNMTs) is an important epigenetic factor regulating gene expression, cell differentiation, cell death, and survival. Previous studies suggested an involvement of epigenetic mechanisms in RP, and in this study, increased cytosine methylation was detected in dying photoreceptors in the rd1, rd2, P23H, and S334ter rodent models for RP. Ultrastructural analysis of photoreceptor nuclear morphology in the rd1 mouse model for RP revealed a severely altered chromatin structure during retinal degeneration that coincided with an increased expression of the DNMT isozyme DNMT3a. To identify disease-specific differentially methylated DNA regions (DMRs) on a genomic level, we immunoprecipitated methylated DNA fragments and subsequently analyzed them with a targeted microarray. Genome-wide comparison of DMRs between rd1 and wild-type retina revealed hypermethylation of genes involved in cell death and survival as well as cell morphology and nervous system development. When correlating DMRs with gene expression data, we found that hypermethylation occurred alongside transcriptional repression. Consistently, motif analysis showed that binding sites of several important transcription factors for retinal physiology were hypermethylated in the mutant model, which also correlated with transcriptional silencing of their respective target genes. Finally, inhibition of DNMTs in rd1 organotypic retinal explants using decitabine resulted in a substantial reduction of photoreceptor cell death, suggesting inhibition of DNA methylation as a potential novel treatment in RP.
Insights
DNA methylation is increased in dying photoreceptors in retinitis pigmentosa (RP) models. Inhibiting DNA methyltransferases (DNMTs) with decitabine reduced photoreceptor cell death, suggesting a new treatment strategy for RP.
Area of Science:
- Epigenetics
- Molecular Biology
- Ophthalmology
Background:
- Retinitis pigmentosa (RP) is an inherited retinal disease causing photoreceptor degeneration and is currently untreatable.
- Understanding the cell death mechanisms in RP is crucial for developing effective treatments.
- Epigenetic modifications, particularly DNA methylation, play a role in gene regulation and cell fate.
Purpose of the Study:
- To investigate the role of DNA methylation in photoreceptor cell death in RP.
- To identify specific DNA methylation patterns associated with RP.
- To explore the therapeutic potential of inhibiting DNA methylation in RP.
Main Methods:
- Analysis of cytosine methylation in photoreceptors from RP rodent models (rd1, rd2, P23H, S334ter).
- Ultrastructural analysis of photoreceptor nuclear morphology and DNMT3a expression in the rd1 mouse model.
- Genome-wide identification of differentially methylated DNA regions (DMRs) using methylated DNA immunoprecipitation and microarray analysis.
- Correlation of DMRs with gene expression data and transcription factor binding sites.
- Inhibition of DNA methyltransferases (DNMTs) using decitabine in rd1 organotypic retinal explants.
Main Results:
- Increased cytosine methylation was observed in dying photoreceptors across multiple RP models.
- Photoreceptor nuclei in the rd1 model showed altered chromatin structure and increased DNMT3a expression.
- Genome-wide analysis revealed hypermethylation of genes involved in cell death, survival, cell morphology, and nervous system development in RP retinas.
- Hypermethylation correlated with transcriptional repression of affected genes and transcription factor binding sites.
- Decitabine treatment significantly reduced photoreceptor cell death in rd1 retinal explants.
Conclusions:
- Aberrant DNA methylation is a key feature of photoreceptor degeneration in RP.
- Hypermethylation of specific genes contributes to the pathogenesis of RP.
- Inhibition of DNA methylation presents a promising therapeutic strategy for treating RP.
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