Sangeetha Vishweswaraiah, Nazia Saiyed, Abdullah Khalid, Milda Milčiūtė, Migle Gabrielaite, Ceyda Buyuker, Boran Aksakal, Lorena Gomes, Juozas Gordevicius, Ali Yilmaz, Stewart F Graham
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引用次数: 0
摘要
血管性认知障碍(VCI)是一种常见的痴呆形式,由大脑血管损伤引起,但其潜在的分子机制尚不清楚。表观遗传修饰,特别是DNA甲基化,与各种神经退行性疾病有关,包括VCI;然而,缺乏这种联系的细节。本研究分析了19例VCI患者和21例对照组的Brodmann area 7组织样本。使用Illumina EPIC V2阵列分析DNA甲基化谱。综合生物信息学方法,包括差异甲基化CpGs (DMCs)、差异甲基化区域(DMRs)和基因集富集分析(GSEA),被用于识别与VCI相关的失调通路。进行了一项性别特异性分析,以探索男性和女性之间甲基化模式的潜在差异。分析显示,3601个CpG位点的甲基化差异显著,在VCI组中观察到主要的高甲基化模式(82%)。值得注意的是,在与神经变性和血管健康相关的关键基因,如MTCH2、DPRX和DENND4A中检测到高甲基化。GSEA确定了与神经元功能和血管健康相关的关键通路。在性别特异性通路分析中,雄性的血管调节机制丰富,雌性的突触可塑性与神经元发育同时存在。与RAB12相关的DMRs强调了溶酶体功能障碍在认知和血管恶化中的作用。我们的发现为VCI的表观遗传景观提供了新的见解,揭示了参与神经元和血管健康的基因的高甲基化。表观遗传模式中性别特异性差异的鉴定强调了定制治疗策略的必要性。这些结果为VCI的早期诊断提供了潜在的生物标志物,并为针对血管和神经元成分的治疗干预提供了新的途径。
Epigenetic Insights into Vascular Cognitive Impairment: DNA Methylation in the Human Brain Tissue.
Vascular cognitive impairment (VCI) is a common form of dementia that results from vascular damage to the brain, yet the underlying molecular mechanisms remain poorly understood. Epigenetic modifications, particularly DNA methylation, have been implicated in various neurodegenerative diseases, including VCI; however, the details of this association are lacking. This study analyzed Brodmann area 7 tissue samples from 19 individuals with VCI and 21 control subjects. DNA methylation profiles were analyzed using the Illumina EPIC array V2. Integrative bioinformatics approaches, including differentially methylated CpGs (DMCs), differentially methylated regions (DMRs), and gene set enrichment analysis (GSEA), were employed to identify dysregulated pathways associated with VCI. A sex-specific analysis was performed to explore potential differences in methylation patterns between males and females. The analysis revealed significant differential methylation across 3601 CpG sites, with a predominant pattern of hypermethylation (82%) observed in the VCI group. Notably, hypermethylation was detected in key genes related to neurodegeneration and vascular health, such as MTCH2, DPRX, and DENND4A. GSEA identified critical pathways related to neuronal function and vascular health. In sex-specific pathway analysis, vascular regulatory mechanisms were enriched in males and synaptic plasticity together with neuronal development in females. DMRs linked to RAB12 highlighted the role of lysosomal dysfunction in both cognitive and vascular deterioration. Our findings provide novel insights into the epigenetic landscape of VCI, revealing hypermethylation of genes involved in both neuronal and vascular health. The identification of sex-specific differences in epigenetic patterns underscores the need for tailored therapeutic strategies. These results offer potential biomarkers for early diagnosis and new avenues for therapeutic intervention targeting both vascular and neuronal components of VCI.
期刊介绍:
Molecular Neurobiology is an exciting journal for neuroscientists needing to stay in close touch with progress at the forefront of molecular brain research today. It is an especially important periodical for graduate students and "postdocs," specifically designed to synthesize and critically assess research trends for all neuroscientists hoping to stay active at the cutting edge of this dramatically developing area. This journal has proven to be crucial in departmental libraries, serving as essential reading for every committed neuroscientist who is striving to keep abreast of all rapid developments in a forefront field. Most recent significant advances in experimental and clinical neuroscience have been occurring at the molecular level. Until now, there has been no journal devoted to looking closely at this fragmented literature in a critical, coherent fashion. Each submission is thoroughly analyzed by scientists and clinicians internationally renowned for their special competence in the areas treated.