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.
Highlights
A previous microarray study showed a dramatic modification in gene expression when the rd1 mouse model for Retinitis pigmentosa (RP) was compared with wild-type animals.2 Such profound effects on gene expression are probably a consequence of both pro-survival responses and induction of cell death pathways
We have previously found the activity of both histone deacetylase (HDAC) and poly-ADP-ribosepolymerase (PARP) to be causally involved in retinal degeneration
It is still unknown if and how DNA methylation patterns vary between different genes in healthy and diseased tissues and whether an interference with DNA methylation would be beneficial for degenerating photoreceptors
Summary
A previous microarray study showed a dramatic modification in gene expression when the rd mouse model for RP was compared with wild-type (wt) animals. Such profound effects on gene expression are probably a consequence of both pro-survival responses and induction of cell death pathways. A previous microarray study showed a dramatic modification in gene expression when the rd mouse model for RP was compared with wild-type (wt) animals.. Alterations of gene expression are often linked to epigenetic events, such as acetylation and poly-ADP-ribosylation of histones In this regard, we have previously found the activity of both histone deacetylase (HDAC) and poly-ADP-ribosepolymerase (PARP) to be causally involved in retinal degeneration.. We have previously found the activity of both histone deacetylase (HDAC) and poly-ADP-ribosepolymerase (PARP) to be causally involved in retinal degeneration.3,4 These epigenetic regulators function via modification of the chromatin structure, direct methylation of the DNA5,6 is another powerful factor in epigenetic regulation of gene expression. All four RP models represent mutations that are similar to the ones found in certain cohorts of patients.
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