Genome-wide DNA methylation profiling in the superior temporal gyrus reveals epigenetic signatures associated with Alzheimer's disease.
Genome-wide DNA methylation profiling in the superior temporal gyrus reveals epigenetic signatures associated with Alzheimer's disease.
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DOI：
10.1186/s13073-015-0258-8
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发表时间：
2016-01-19
期刊：
影响因子：
12.3
通讯作者：
Sharp AJ
中科院分区：
文献类型：
--
作者：
Watson CT;Roussos P;Garg P;Ho DJ;Azam N;Katsel PL;Haroutunian V;Sharp AJ
阿尔茨海默病影响美国65岁及以上人群的约13%，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。我们使用Illumina Infinium HumanMethylation 450平台对来自阿尔茨海默病患者和非痴呆对照的上级颞回的大量组织样本进行了全基因组DNA甲基化筛选。我们配对的滑动窗口方法与多元线性回归，以表征阿尔茨海默病相关的差异甲基化区域（DMR）。我们确定了479个DMR表现出强烈的偏置高甲基化的变化，其中一个子集是独立与老化。DMR间隔与475个RefSeq基因重叠，这些基因富集了在神经元功能和发育以及细胞代谢中具有相关作用的基因本体论类别，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富集了脑特异性组蛋白特征和在脑和阿尔茨海默病病理学中起作用的转录因子的结合基序。值得注意的是，高甲基化的DMR优先重叠平衡的启动子区域，标记为H3 K27 me 3和H3 K4 me 3，以前显示与衰老相关的高甲基化共定位。最后，DMR相关的单核苷酸多态性与阿尔茨海默病全基因组关联研究风险基因座和脑表达数量性状基因座的整合突出了多个潜在的DMR的进一步功能分析的兴趣。我们已经表征了阿尔茨海默病患者的上级颞回中DNA甲基化的变化，突出了有助于更好地表征阿尔茨海默病发病机制的途径和机制的新位点，并提高了我们对可能有助于疾病发展的表观遗传特征的理解。本文的在线版本（doi：10.1186/s13073-015-0258-8）包含补充材料，可供授权用户使用。
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. 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). 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. 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. The online version of this article (doi:10.1186/s13073-015-0258-8) contains supplementary material, which is available to authorized users.