Abstract

Age-related macular degeneration (AMD) is a chronic, multifactorial disorder and a leading cause of blindness in the elderly. Characterized by progressive photoreceptor degeneration in the central retina, disease progression involves epigenetic changes in chromatin accessibility resulting from environmental exposures and chronic stress. Here, we report that a photosensitive mouse model of acute stress-induced photoreceptor degeneration recapitulates the epigenetic hallmarks of human AMD. Global epigenomic profiling was accomplished by employing an Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-Seq), which revealed an association between decreased chromatin accessibility and stress-induced photoreceptor cell death in our mouse model. The epigenomic changes induced by light damage include reduced euchromatin and increased heterochromatin abundance, resulting in transcriptional and translational dysregulation that ultimately drives photoreceptor apoptosis and an inflammatory reactive gliosis in the retina. Of particular interest, pharmacological inhibition of histone deacetylase 11 (HDAC11) and suppressor of variegation 3–9 homolog 2 (SUV39H2), key histone-modifying enzymes involved in promoting reduced chromatin accessibility, ameliorated light damage in our mouse model, supporting a causal link between decreased chromatin accessibility and photoreceptor degeneration, thereby elucidating a potential new therapeutic strategy to combat AMD.

中文翻译：

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勘误表：伴侣蛋白伴侣和还原酶ERdj5促进杆视蛋白的生物发生和质量控制。

摘要

年龄相关性黄斑变性（AMD）是一种慢性多因素疾病，是老年人失明的主要原因。疾病进展的特征是中央视网膜进行性光感受器变性，疾病进展涉及环境暴露和慢性应激导致的染色质可及性的表观遗传变化。在这里，我们报告说，急性应激诱导的光感受器变性的光敏小鼠模型概括了人类AMD的表观遗传学特征。通过采用测序技术（ATAC-Seq）对转座酶可及的染色质进行分析（ATAC-Seq），完成了全球表观基因组分析，结果表明在我们的小鼠模型中，染色质可及性降低与应激诱导的感光细胞死亡之间存在关联。由光损伤引起的表观基因组变化包括常染色质减少和异染色质丰度增加，导致转录和翻译失调，最终导致感光细胞凋亡和视网膜中的炎症反应性胶质细胞增生。特别令人感兴趣的是，对组蛋白脱乙酰基酶11（HDAC11）和变体3–9同源物2的抑制物（SUV39H2），是关键的组蛋白修饰酶，参与促进染色质可及性的降低，减轻了小鼠模型的光损伤，支持了染色质可及性与光感受器变性之间的因果关系，从而阐明了对抗AMD的潜在新治疗策略。