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Updated: Jun 13, 2025
Electroporation-Based Genetic Modification of Primary Human Pigment Epithelial Cells Using the Sleeping Beauty Transposon System
Published on: February 4, 2021
Epigenetic modifiers to treat retinal degenerative diseases
Abstract:
We have previously demonstrated the ability of inhibitors of LSD1 and HDAC1 to block rod degeneration, preserve vision, maintain rod-specific transcripts and downregulate those involved in inflammation, gliosis, and cell death in the rd10 mouse model of Retinitis Pigmentosa (RP). 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 G9A/GLP that catalyzes methylation of H3K9, for EZH2 that catalyzes trimethylation of H3K27, and compared them to the actions of inhibitors of LSD1 and HDAC. All the inhibitors 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 Ca +2 and Wnt signaling pathways with 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 down-regulating 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, including LSD1, HDAC1, G9A/GLP, and EZH2, prevents rod cell death in the rd10 mouse model of Retinitis Pigmentosa (RP). These treatments preserve retinal structure and function by altering gene expression related to cell survival and inflammation.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Retinitis Pigmentosa (RP) is a group of inherited retinal diseases causing progressive vision loss.
- The rd10 mouse model exhibits photoreceptor degeneration, making it a valuable tool for studying RP.
- Previous studies showed LSD1 and HDAC1 inhibitors can protect rod photoreceptors in rd10 mice.
Purpose of the Study:
- To investigate if inhibiting chromatin condensation can prevent photoreceptor degeneration in the rd10 mouse model.
- To explore the effects of various chromatin condensation inhibitors (G9A/GLP, EZH2, LSD1, HDAC1) on retinal health.
Main Methods:
- Utilized rd10 mice, a model for Retinitis Pigmentosa.
- Administered inhibitors targeting chromatin condensation: G9A/GLP (H3K9 methylation), EZH2 (H3K27 trimethylation), LSD1, and HDAC1.
- Assessed retinal preservation, vision maintenance, and changes in gene expression profiles.
Main Results:
- All tested chromatin condensation inhibitors decondensed chromatin and preserved retinas to varying degrees in rd10 mice.
- LSD1 and EZH2 inhibitors maintained rod-specific transcripts, activated Ca+2 and Wnt pathways, and inhibited immune responses.
- HDAC and G9A/GLP inhibitors upregulated NGF-stimulated transcription while downregulating immune response, extracellular matrix, cholesterol signaling, and programmed cell death genes.
Conclusions:
- Inhibition of chromatin condensation is sufficient to prevent rod death in the rd10 mouse model of RP.
- Different chromatin modifiers act through distinct metabolic pathways to achieve photoreceptor protection.
- These findings support chromatin structure alteration as a therapeutic strategy for RP.
