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. 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.

神经退行性疾病通常以拉伸指数速率分布（stretched exponential rate/distribution）的模式呈现进行性细胞丢失。群体中部分克隆细胞的存活时长超出随机预期的背后机制仍未阐明。为探究细胞长期存活的潜在机制，我们以Spata7突变小鼠（Spata7 mutant mice）为模型，对视网膜组织在光感受器变性的时间进程中开展了单细胞转录组分析（single-cell transcriptomic profiling）。有趣的是，在初始快速细胞凋亡阶段后存活的视杆细胞，会逐渐获得独特的转录组特征。在这些存活的视杆细胞中，光感受器特异性光转导通路基因的表达被下调，而其他视网膜细胞类型特异性标记基因的表达则被上调。正如免疫荧光染色（immunofluorescence staining）与单细胞ATAC-seq（single-cell ATAC-seq）所揭示的，此类转录组变化是通过直接调控这些基因位点的表观基因组修饰与染色质状态改变实现的。与该模型一致，当通过体内组蛋白去乙酰化酶（HDAC, histone deacetylase）抑制阻断抑制性表观状态的诱导过程时，突变小鼠视网膜内的所有视杆细胞都会发生快速变性，大幅缩减了拉伸指数分布的范围。综上，本研究揭示了一种内在机制：神经元细胞可通过表观基因组调控与染色质状态重塑，逐步适应遗传应激以实现长期存活。为全面解析视网膜组织在光感受器变性进程中的相关特征，我们分别于第1、3、6个月采集野生型与Spata7基因敲除突变小鼠的视网膜细胞，开展了单细胞RNA测序。我们以Spata7突变小鼠为模型。为全面解析视网膜组织在光感受器变性进程中的相关特征，我们分别采集7月龄野生型与6月龄Spata7基因敲除突变小鼠的视网膜细胞，开展了单细胞ATAC测序。