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Epigenetic Modifiers to Treat Retinal Degenerative Diseases
Evgenya Y Popova1, Lisa Schneper2, Aswathy Sebastian3
1Department of Neuroscience, Penn State University College of Medicine, Hershey, PA 17033, USA.
Abstract:
We have previously demonstrated the ability of inhibitors of LSD1 and HDAC1 to block rod degeneration, preserve vision, maintain transcription of rod photoreceptor genes, and downregulate transcripts involved in cell death, gliosis, and inflammation in the mouse model of Retinitis Pigmentosa (RP), rd10. To extend our findings, we tested the hypothesis that this effect was due to altered chromatin structure by using a range of inhibitors of chromatin condensation to prevent photoreceptor degeneration in the rd10 mouse model. We used inhibitors for both G9A/GLP, which catalyzes methylation of H3K9, and EZH2, which catalyzes trimethylation of H3K27, and compared them to the actions of inhibitors of LSD1 and HDAC. All the inhibitors are likely to decondense chromatin and all preserve, to different extents, retinas from degeneration in rd10 mice, but they act through different metabolic pathways. One group of inhibitors, modifiers for LSD1 and EZH2, demonstrate a high level of maintenance of rod-specific transcripts, activation of Ca2+ and Wnt signaling pathways with the inhibition of antigen processing and presentation, immune response, and microglia phagocytosis. Another group of inhibitors, modifiers for HDAC and G9A/GLP, work through upregulation of NGF-stimulated transcription, while downregulating genes belong to immune response, extracellular matrix, cholesterol signaling, and programmed cell death. Our results provide robust support for our hypothesis that inhibition of chromatin condensation can be sufficient to prevent rod death in rd10 mice.
Insights
Inhibiting chromatin condensation prevents photoreceptor degeneration in a mouse model of Retinitis Pigmentosa (RP). This approach preserves vision by maintaining rod photoreceptor gene transcription and reducing cell death pathways.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Retinitis Pigmentosa (RP) is a group of inherited diseases that cause vision loss.
- Previous studies showed LSD1 and HDAC1 inhibitors can prevent rod degeneration in the rd10 mouse model of RP.
- The mechanism underlying this protection may involve altered chromatin structure.
Purpose of the Study:
- To test the hypothesis that inhibiting chromatin condensation prevents photoreceptor degeneration in the rd10 mouse model.
- To investigate the effects of various chromatin condensation inhibitors, including those targeting G9A/GLP and EZH2, on photoreceptor survival.
Main Methods:
- Utilized inhibitors targeting G9A/GLP (H3K9 methylation) and EZH2 (H3K27 trimethylation).
- Compared these inhibitors with those targeting LSD1 and HDAC.
- Administered inhibitors to rd10 mice to assess their impact on photoreceptor degeneration.
Main Results:
- All tested inhibitors, likely decondensing chromatin, preserved retinas to varying degrees in rd10 mice.
- LSD1 and EZH2 inhibitors maintained rod-specific transcripts and activated Ca2+ and Wnt signaling, while inhibiting immune responses.
- HDAC and G9A/GLP inhibitors upregulated NGF-stimulated transcription and downregulated immune response, extracellular matrix, cholesterol signaling, and cell death genes.
Conclusions:
- Inhibition of chromatin condensation is sufficient to prevent rod death in the rd10 mouse model.
- Different chromatin modifiers act through distinct pathways to protect photoreceptors.
- These findings support chromatin structure modulation as a therapeutic strategy for RP.
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