The fusiform gyrus exhibits an epigenetic signature for Alzheimer's disease
The fusiform gyrus exhibits an epigenetic signature for Alzheimer's disease
复制标题
DOI：
10.1186/s13148-020-00916-3
复制
发表时间：
2020-08-27
影响因子：
5.7
通讯作者：
Shi, Yujiang G.
中科院分区：
文献类型：
--
作者：
Ma, Dingailu;Fetahu, Irfete S.;Shi, Yujiang G.
背景阿尔茨海默病 (AD) 是最常见的痴呆症类型，晚期 AD 患者经常丧失识别家庭成员的能力。大脑的梭状回（FUS）对于面部识别至关重要。然而，人们对 AD 患者 FUS 的 AD 病因知之甚少。需要新的分析策略来揭示 FUS 中 AD 的遗传和表观遗传基础。结果使用一系列新的分析范式，整合了正常对照、AD 患者的一系列转录组和甲基化组以及“AD 培养皿”模型，用于在 FUS 中鉴定 AD 的遗传和表观遗传特征。在这里，我们发现了 AD 患者大脑中 FUS 特有的基因表达变化。这些变化与 AD 网络中的关键基因密切相关。在碱基分辨率下对甲基化组 (5mC/5hmC/5fC/5caC) 进行分析，确定了 5 个特征基因 (COL2A1、CAPN3、COL14A1、STAT5A、SPOCK3)，这些基因表现出表达紊乱，特别是在 FUS 中，并显示出 AD 相关脑区常见的 DNA 甲基化组谱改变。此外，我们证明了原理证明，与目前使用的临床标准相比，这些基因中与 AD 相关的甲基化组变化可以有效预测疾病预后，且敏感性更高。结论 本研究鉴定了一组先前未探索的 FUS 特异性 AD 基因及其表观遗传特征，这可能为 AD 的分子病理学提供新的见解，将 FUS 的遗传和表观遗传基础归因于 AD 的发展。
Background Alzheimer's disease (AD) is the most common type of dementia, and patients with advanced AD frequently lose the ability to identify family members. The fusiform gyrus (FUS) of the brain is critical in facial recognition. However, AD etiology in the FUS of AD patients is poorly understood. New analytical strategies are needed to reveal the genetic and epigenetic basis of AD in FUS. Results A complex of new analytical paradigms that integrates an array of transcriptomes and methylomes of normal controls, AD patients, and "AD-in-dish" models were used to identify genetic and epigenetic signatures of AD in FUS. Here we identified changes in gene expression that are specific to the FUS in brains of AD patients. These changes are closely linked to key genes in the AD network. Profiling of the methylome (5mC/5hmC/5fC/5caC) at base resolution identified 5 signature genes (COL2A1,CAPN3,COL14A1,STAT5A,SPOCK3) that exhibit perturbed expression, specifically in the FUS and display altered DNA methylome profiles that are common across AD-associated brain regions. Moreover, we demonstrate proof-of-principle that AD-associated methylome changes in these genes effectively predict the disease prognosis with enhanced sensitivity compared to presently used clinical criteria. Conclusions This study identified a set of previously unexplored FUS-specific AD genes and their epigenetic characteristics, which may provide new insights into the molecular pathology of AD, attributing the genetic and epigenetic basis of FUS to AD development.