进行性核上性麻痹脑组织中MAPT基因甲基化的差异
The MAPT gene is differentially methylated in the progressive supranuclear palsy brain
摘要：
背景：进行性核上性麻痹（PSP）是一种罕见的神经退行性疾病，引起帕金森症状。微管相关蛋白tau基因的DNA甲基化改变与阿尔茨海默病和帕金森病大脑中的表达变化相关目的：由于通过甲基化激活不同的微管相关蛋白tau基因控制区可能调节tau蛋白的差异表达，从而构成个体tau蛋白病的特异性特征，我们比较了候选启动子内含子0的甲基化。方法：我们通过内含子0焦磷酸测序评估了不同tau蛋白病患者（35例阿尔茨海默病，10例皮质基底节变性和18例PSP）和19例对照组大脑中的DNA甲基化。我们还评估了11例PSP病例和12例对照的独立队列中的甲基化。额叶（受tau病理）和枕叶（未受影响）cortex.Results：在最初的样品中，一个CpG岛网站内含子0（CpG 1）显示出显着的低甲基化PSP影响的额叶皮质相比，与对照组（p = 0.022）。在重复样品中观察到这种低甲基化，但在枕叶皮质或其他tau蛋白病中未观察到。PSP和对照样本（合并初始和重复样本）在调整潜在混杂因素（年龄，H1/H1双倍型; p = 0.0005）后仍存在显著差异。PSP影响的组织表现出微管相关蛋白tau RNA高表达时，与对照组相比（p = 0.004），虽然没有相关性与CpG 1甲基化observed.Conclusions：这项探索性研究表明，区域以外的组成型启动子可能参与微管相关蛋白tau蛋白基因调控在tau蛋白病和内含子0低甲基化可能是一个特定的表观遗传特征的PSP。这些初步调查结果需要确认。
英文摘要：
Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease causing parkinsonian symptoms. Altered DNA methylation of the microtubule-associated protein tau gene correlates with the expression changes in Alzheimer's disease and Parkinson's disease brains. However, few studies examine the sequences beyond the constitutive promoter.Objectives: Because activating different microtubule associated protein tau gene control regions via methylation might regulate the differential tau expression constituting the specific signatures of individual tauopathies, we compared methylation of a candidate promoter, intron 0.Methods: We assessed DNA methylation in the brains of patients with different tauopathies (35 Alzheimer's disease, 10 corticobasal degeneration, and 18 PSP) and 19 controls by intron 0 pyrosequencing. We also evaluated methylation in an independent cohort of 11 PSP cases and 12 controls. Frontal (affected by tau pathology) and occipital (unaffected) cortices were analyzed.Results: In the initial samples, one CpG island site in intron 0 (CpG1) showed significant hypomethylation in PSP-affected frontal cortices when compared with controls (p = 0.022). Such hypomethylation was observed in replicate samples, but not in occipital cortices or other tauopathies. PSP and control samples (combining the initial and replicate samples) remained significantly different after adjustment for potential confounding factors (age, H1/H1 diplotype; p = 0.0005). PSP-affected tissues exhibited microtubule-associated protein tau RNA hyperexpression when compared with controls (p = 0.004), although no correlation with CpG1 methylation was observed.Conclusions: This exploratory study suggests that regions other than the constitutive promoter may be involved in microtubule-associated protein tau gene regulation in tauopathies and that intron 0 hypomethylation may be a specific epigenetic signature of PSP. These preliminary findings require confirmation.
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