DNA Methylation Dynamics in a Mouse Model of Retinitis Pigmentosa.

IF 4.7 2区 医学 Q1 PATHOLOGY
Lu Huang, Lydia Tai Wai, Kin-Sang Cho, Ajay Ashok, Maximilian Braun, Menglu Yang, Karen Chang, Anton Lennikov, Sarita Pooranawattanakul, Farris Elzaridi, Hio Tong Kam, Yizhen Tang, Qingfeng Li, Dong Feng Chen
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引用次数: 0

Abstract

Retinitis pigmentosa (RP) is a group of sight-threatening genetic diseases characterized by progressive degeneration of photoreceptors, leading to severe vision loss from childhood to the adult. With limited treatment options, understanding the molecular mechanisms underlying RP is crucial. Evidence points to increased DNA methylation, especially in degenerating photoreceptors, as a contributing factor to retinal damage in RP. To exploit the molecular insights into methylation-driven pathways, this study investigates the DNA methylation patterns and their potential roles in photoreceptor degeneration in a mouse model of RP, specifically mice carrying a rhodopsin deficiency (Rho-/-). We observed elevated levels of DNA methyltransferases (DNMTs) and DNA methylation during photoreceptor degeneration. Importantly, weekly intravitreal injections of the pan DNMT inhibitor decitabine in Rho-/- mice significantly improved photoreceptor morphology and visual function, as evidenced by electroretinogram, spectral-domain optical coherence tomography, and optomotor response-based visual behavior assays. Further histological and immunohistochemical assessments revealed increased survival of cone photoreceptors and thicker outer nuclear layers in decitabine-treated mice compared to controls. Together, these findings reveal that the dynamics of DNA methylation correlate with photoreceptor degeneration. Inhibition of DNMTs mitigated the morphological and functional impairments associated with the genetic defects in photoreceptors, suggesting that targeting DNA methylation could be a viable therapeutic strategy for neuroprotection in RP.

色素性视网膜炎小鼠模型的DNA甲基化动力学。
色素性视网膜炎(RP)是一组以光感受器进行性变性为特征的威胁视力的遗传性疾病,可导致儿童期至成年期的严重视力丧失。由于治疗方案有限,了解RP的分子机制至关重要。有证据表明,DNA甲基化增加,特别是在退化的光感受器中,是RP视网膜损伤的一个促进因素。为了探索甲基化驱动途径的分子见解,本研究调查了DNA甲基化模式及其在RP小鼠模型中的潜在作用,特别是携带视紫红质缺陷(Rho-/-)的小鼠。我们观察到在光感受器变性过程中DNA甲基转移酶(dnmt)和DNA甲基化水平升高。重要的是,每周在Rho-/-小鼠玻璃体内注射pan DNMT抑制剂地西他滨可显著改善光感受器形态和视觉功能,视网膜电图、光谱域光学相干断层扫描和基于视动反应的视觉行为分析证明了这一点。进一步的组织学和免疫组织化学评估显示,与对照组相比,地西他滨治疗小鼠的视锥光感受器存活率增加,外核层更厚。总之,这些发现揭示了DNA甲基化的动力学与光感受器变性相关。dnmt的抑制减轻了与光感受器遗传缺陷相关的形态学和功能损伤,表明靶向DNA甲基化可能是RP神经保护的一种可行的治疗策略。
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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
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