当前位置: X-MOL 学术Genome Med. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Genome-wide DNA methylation profiling in the superior temporal gyrus reveals epigenetic signatures associated with Alzheimer's disease.
Genome Medicine ( IF 10.4 ) Pub Date : 2016-01-19 , DOI: 10.1186/s13073-015-0258-8
Corey T Watson 1 , Panos Roussos 1, 2, 3 , Paras Garg 1 , Daniel J Ho 1 , Nidha Azam 1 , Pavel L Katsel 2, 4 , Vahram Haroutunian 2, 3, 4 , Andrew J Sharp 1
Affiliation  

BACKGROUND Alzheimer's disease affects ~13% of people in the United States 65 years and older, making it the most common neurodegenerative disorder. Recent work has identified roles for environmental, genetic, and epigenetic factors in Alzheimer's disease risk. METHODS We performed a genome-wide screen of DNA methylation using the Illumina Infinium HumanMethylation450 platform on bulk tissue samples from the superior temporal gyrus of patients with Alzheimer's disease and non-demented controls. We paired a sliding window approach with multivariate linear regression to characterize Alzheimer's disease-associated differentially methylated regions (DMRs). RESULTS We identified 479 DMRs exhibiting a strong bias for hypermethylated changes, a subset of which were independently associated with aging. DMR intervals overlapped 475 RefSeq genes enriched for gene ontology categories with relevant roles in neuron function and development, as well as cellular metabolism, and included genes reported in Alzheimer's disease genome-wide and epigenome-wide association studies. DMRs were enriched for brain-specific histone signatures and for binding motifs of transcription factors with roles in the brain and Alzheimer's disease pathology. Notably, hypermethylated DMRs preferentially overlapped poised promoter regions, marked by H3K27me3 and H3K4me3, previously shown to co-localize with aging-associated hypermethylation. Finally, the integration of DMR-associated single nucleotide polymorphisms with Alzheimer's disease genome-wide association study risk loci and brain expression quantitative trait loci highlights multiple potential DMRs of interest for further functional analysis. CONCLUSION We have characterized changes in DNA methylation in the superior temporal gyrus of patients with Alzheimer's disease, highlighting novel loci that facilitate better characterization of pathways and mechanisms underlying Alzheimer's disease pathogenesis, and improve our understanding of epigenetic signatures that may contribute to the development of disease.

中文翻译:

颞上回全基因组 DNA 甲基化分析揭示了与阿尔茨海默病相关的表观遗传特征。

背景阿尔茨海默病影响约 13% 的美国 65 岁及以上人群,使其成为最常见的神经退行性疾病。最近的工作已经确定了环境、遗传和表观遗传因素在阿尔茨海默病风险中的作用。方法 我们使用 Illumina Infinium HumanMmethylation450 平台对阿尔茨海默病患者和非痴呆对照者颞上回的大量组织样本进行了全基因组 DNA 甲基化筛查。我们将滑动窗口方法与多元线性回归配对来表征阿尔茨海默病相关的差异甲基化区域(DMR)。结果我们确定了 479 个 DMR,它们表现出强烈的高甲基化变化倾向,其中一部分与衰老独立相关。DMR 区间重叠了 475 个 RefSeq 基因,这些基因丰富了基因本体类别,在神经元功能和发育以及细胞代谢中具有相关作用,并包括阿尔茨海默病全基因组和表观基因组关联研究中报告的基因。DMR 富含大脑特异性组蛋白特征以及在大脑和阿尔茨海默病病理学中发挥作用的转录因子的结合基序。值得注意的是,高甲基化的 DMR 优先与以 H3K27me3 和 H3K4me3 为标志的平衡启动子区域重叠,先前显示这些区域与衰老相关的高甲基化共定位。最后,DMR 相关单核苷酸多态性与阿尔茨海默病全基因组关联研究风险位点和大脑表达数量性状位点的整合突出了多个潜在的 DMR,可用于进一步的功能分析。结论 我们已经表征了阿尔茨海默病患者颞上回 DNA 甲基化的变化,突出了新的位点,这些位点有助于更好地表征阿尔茨海默病发病机制的途径和机制,并提高我们对可能有助于疾病发展的表观遗传特征的理解。
更新日期:2019-11-01
down
wechat
bug