Epigenetic modifiers to treat retinal degenerative diseases.
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 broad range of inhibitors of chromatin condensation can 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 LSD1 and HDAC inhibitors. All the inhibitors decondense chromatin and all preserve, to different extents, retinas from degeneration in rd10mice, 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. Overall design: Total 26 samples of mouse retina at PN24 in 5 groups: 1). 3 controls  B6.CXB1-Pde6brd10/Jrd10 (rd10) and 3 rd10 treated with HDAC inhibitor Romidepsin from PN9 till PN24; 2). 2 rd10 controls and 2 rd10 treated with G9A/GLP inhibitor UNC0642 from PN9 till PN24; 3). 4 rd10 controls and 2 rd10 treated with EZH2 inhibitor DZNep from PN9 till PN24; 4). 3 rd10 controls and 3 rd10 treated with EZH2 inhibitor UNC1999 from PN9 till PN24; 5). 2 controls FACS sorted rod photoreceptors from homozygotes mice of cross between rd10 and B6.Cg-Tg(Nrl-EGFP)1Asw/J and 2 littermates treated from PN9 till PN24 with LSD1 inhibitor GSK2879552.