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Arshan Perera, Susanne Koch, Martin Biel, Stylianos Michalakis; Hyperhydroxymethylation in rd1 retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5000.
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The removal of DNA methylation in neurons via hydroxylation of Tet enzymes has been implicated in gene regulation and active DNA demethylation. Although, recent studies suggest that DNA methylation is crucial for cell homeostasis, the exact mechanisms how DNA methylation contributes to cell death are still unknown. Here, we investigated the role of 5hmC during retinal degeneration in rd1 mice.
We labelled and quantified 5hmC and TdT-mediated dUTP-biotin nick end labeling (TUNEL) positive rod photoreceptors in rd1 mice using immunohistochemistry. Next, we mapped 5hmC marks to the retinal genome by hydroxymethylated DNA immunoprecipitation (hMeDIP) followed by next generation sequencing (NGS) in rd1 and wildtype mice. Finally, we performed a correlation analysis of 5hmC-enriched genes in rd1 mice with microarray gene expression data.
At the peak time points of rod photoreceptor degeneration in rd1 mice, we detected elevated levels of 5hmC in rod photoreceptors. Interestingly, we detected a positive correlation of TUNEL positive rod photoreceptors and increased 5hmC levels. The hMeDIP data revealed an acquisition of 5hmC at gene-rich regions. Moreover, gene ontology analysis showed that 5hmC-enriched genes are involved in neurological diseases. Correlation of our hMeDIP data with microarray data revealed that hyperhydroxymethylation in the rd1 retina was accompanied with increased gene expression of the corresponding genes.
Our findings show that 5hmC is enriched in degenerating rod photoreceptors and may contribute to an epigenetically programmed cell death pathway via target activation of cell death-related genes. In summary, our data provide novel insights into the role of 5hmC as an epigenetic regulator during neurodegeneration.
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