Epigenetic adaptation prolongs photoreceptor survival during retinal degeneration

Neural degenerative diseases often display a progressive loss of cells at as a stretched exponential ratedistribution. The mechanisms underlying the survival of a subset of clonal cells in a population beyond what is expected by chance alone remains unknown. To gain mechanistic insights underlying prolonged cellular survival, we used Spata7 mutant mice as a model and performed single-cell transcriptomic profiling of retinal tissue along the time course of photoreceptor degeneration. Intriguingly, rod cells that survive beyond the initial rapid cell apoptosis phase progressively acquire a distinct transcriptome profile. In these rod cells, expression of photoreceptor-specific phototransduction pathway genes is downregulated while expression of other retinal cell type-specific marker genes is upregulated. These transcriptomic changes are achieved by direct modulation of the epigenomeetic modifications and changes of the chromatin state at these gene loci, as indicated by immunofluorescence staining and single-cell ATAC-seq. Consistent with this model, when the induction of the repressive epigenetic state is blocked by in vivo histone deacetylase HDAC inhibition, all photoreceptors in the mutant retina undergo rapid degeneration, strongly curtailing the stretched exponential distribution. Altogether, oOur study reveals an intrinsic mechanism by which the neuralon cells progressively adapt to the genetic stress to achieve prolonged survival through epigenomic regulation and chromatin state modulation. Overall design: To globally characterize the of retinal tissue along the time course of photoreceptor degeneration, we performed single cell RNA sequencing of retinal cells from wild type and Spata7 knockout mutant mice at 1, 3, 6 month. we used Spata7 mutant mice as a model. To globally characterize the of retinal tissue along the time course of photoreceptor degeneration, we performed single cell ATAC sequencing of retinal cells from 7M wild type and 6M Spata7 knockout mutant mice.