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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在光敏小鼠模型中概括了年龄相关性黄斑变性的表观遗传特征。

年龄相关性黄斑变性 (AMD) 是一种慢性、多因素疾病，是导致老年人失明的主要原因。疾病进展的特点是中央视网膜进行性光感受器变性，涉及环境暴露和慢性压力导致染色质可及性的表观遗传变化。在这里，我们报告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 的表观遗传特征。全球表观基因组分析是通过使用测序（ATAC-Seq）对转座酶可接近的染色质进行检测来完成的，这揭示了我们的小鼠模型中染色质可接近性降低与应激诱导的光感受器细胞死亡之间的关联。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，最终驱动光感受器细胞凋亡和视网膜中的炎症反应性神经胶质增生。特别令人感兴趣的是，药理抑制组蛋白去乙酰化酶 11 (HDAC11)和杂色抑制因子 3-9 同系物 2 (SUV39H2)，关键的组蛋白修饰酶参与促进染色质可及性降低，改善我们小鼠模型中的光损伤，支持染色质可及性降低和光感受器变性之间的因果关系，从而阐明了一种潜在的新治疗策略来对抗 AMD。