阿尔茨海默病大脑DNA羟甲基化的全基因组分析。
A genome-wide profiling of brain DNA hydroxymethylation in Alzheimer's disease.
作者信息
Zhao Jinying, Zhu Yun, Yang Jingyun, Li Lin, Wu Hao, De Jager Philip L, Jin Peng, Bennett David A
机构信息
Department of Epidemiology, College of Public Health and Health Professions, University of Florida, Gainesville, FL, USA.
Department of Epidemiology, College of Public Health and Health Professions, University of Florida, Gainesville, FL, USA.
出版信息
Alzheimers Dement. 2017 Jun;13(6):674-688. doi: 10.1016/j.jalz.2016.10.004. Epub 2017 Jan 6.
INTRODUCTION
DNA methylation is a key epigenetic mechanism in brain aging and Alzheimer's disease (AD). The newly discovered 5-hydroxymethylcytosine mediates DNA demethylation, is highly abundant in the brain, and is dynamically regulated by life experiences. However, little is known about its genome-wide patterns and potential role in AD.
METHODS
Using a genome-wide capture followed by high-throughput sequencing, we studied the genome-wide distribution of 5-hydroxymethylcytosine at specific genomic loci in human AD brain and identified differentially hydroxymethylated regions (DhMRs) associated with AD pathology.
RESULTS
We identified 517 DhMRs significantly associated with neuritic plaques and 60 DhMRs associated with neurofibrillary tangles. DNA hydroxymethylation in gene bodies was predominantly positively correlated with cis-acting gene expression. Moreover, genes showing differential hydroxymethylation were significantly enriched in neurobiological processes and clustered in functional gene ontology categories.
DISCUSSION
Our results reveal a critical role of DNA hydroxymethylation in AD pathology and provide mechanistic insight into the molecular mechanisms underlying AD.
引言
DNA甲基化是大脑衰老和阿尔茨海默病（AD）中的关键表观遗传机制。新发现的5-羟甲基胞嘧啶介导DNA去甲基化，在大脑中高度丰富，并受生活经历动态调控。然而，其全基因组模式及其在AD中的潜在作用却鲜为人知。
方法
采用全基因组捕获结合高通量测序，我们研究了人类AD大脑中特定基因组位点的5-羟甲基胞嘧啶全基因组分布，并鉴定了与AD病理相关的差异羟甲基化区域（DhMRs）。
结果
我们鉴定出517个与神经炎性斑块显著相关的DhMRs和60个与神经原纤维缠结相关的DhMRs。基因体内的DNA羟甲基化主要与顺式作用基因表达呈正相关。此外，显示差异羟甲基化的基因在神经生物学过程中显著富集，并聚集在功能基因本体类别中。
讨论
我们的结果揭示了DNA羟甲基化在AD病理中的关键作用，并为AD潜在的分子机制提供了机理见解。
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