Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease.
Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease.
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DOI：
10.1073/pnas.1707151114
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发表时间：
2017-11-07
影响因子：
11.1
通讯作者：
Iwata A
中科院分区：
文献类型：
--
作者：
Mano T;Nagata K;Nonaka T;Tarutani A;Imamura T;Hashimoto T;Bannai T;Koshi-Mano K;Tsuchida T;Ohtomo R;Takahashi-Fujigasaki J;Yamashita S;Ohyagi Y;Yamasaki R;Tsuji S;Tamaoka A;Ikeuchi T;Saido TC;Iwatsubo T;Ushijima T;Murayama S;Hasegawa M;Iwata A
为了从阿尔茨海默病（AD）死后大脑中提取可能丢失的关键信息，我们选择筛选表观遗传特征。表观基因组分析在其细胞类型和基因特异性、高通量分析的适用性和对死后降解的抗性方面是一种稳健的方法。对神经元特异性甲基化组的分析揭示了多种差异甲基化基因，包括BRCA1。我们通过分析BRCA 1对淀粉样蛋白β（Aβ）诱导的DNA双链断裂的神经保护功能，证明了基因组完整性受损的致病相关性。此外，BRCA1在聚集的tau存在下的不溶性表明了尽管表达增强但其功能障碍的原因。我们提供了深入了解AD的病理机制，并展示了筛选神经元特异性甲基化组以揭示新的致病因素的潜力。阿尔茨海默病（Alzheimer's disease，AD）是一种以β淀粉样蛋白（amyloid β，Aβ）和磷酸化tau蛋白在脑内聚集为特征的慢性神经退行性疾病。脑内的死后降解和细胞复杂性限制了从分子上定义AD病理特征和神经元功能障碍之间因果关系的方法。为了克服这些局限性，我们分析了AD患者死后大脑样本的神经元特异性DNA甲基化组，这使得BRCA1启动子的差异低甲基化区域得以鉴定。BRCA1的表达在AD脑中显著上调，与其低甲基化一致。Aβ诱导的DNA损伤也会导致BRCA 1蛋白水平升高。BRCA1以tau依赖性方式错误定位于细胞质并且高度不溶，导致体外细胞和体内小鼠模型中的DNA片段化。Aβ负荷下BRCA 1功能障碍与伴随的基因组完整性和突触可塑性恶化一致。AD模型小鼠大脑的Brca 1启动子区域也同样低甲基化，表明AD中BRCA 1调控的表观遗传机制。我们的研究结果表明，恶化的DNA完整性作为一个核心的贡献因素，在AD的发病机制。此外，这些数据证明了使用神经元特异性DNA甲基化组分析来促进发现散发性神经退行性疾病的病因候选者的技术可行性。
To extract critical information from Alzheimer’s disease (AD) postmortem brains that may otherwise be lost, we chose to screen epigenetic signatures. Epigenome analysis is a robust methodology in terms of its cell type and gene specificity, suitability for high-throughput analysis, and resistance to postmortem degradation. Analysis of the neuron-specific methylome revealed a variety of differentially methylated genes, including BRCA1. We demonstrate the pathogenic relevance of compromised genomic integrity by analyzing the neuroprotective function of BRCA1 against amyloid β (Aβ)-induced DNA double-strand breaks. Furthermore, insolubility of BRCA1 under the presence of aggregated tau suggested the reason for its dysfunction despite enhanced expression. We provide insight into the pathomechanism of AD and demonstrate the potential of screening neuron-specific methylome to reveal new pathogenic contributors. Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid β (Aβ) and phosphorylated tau proteins in the brain. Postmortem degradation and cellular complexity within the brain have limited approaches to molecularly define the causal relationship between pathological features and neuronal dysfunction in AD. To overcome these limitations, we analyzed the neuron-specific DNA methylome of postmortem brain samples from AD patients, which allowed differentially hypomethylated region of the BRCA1 promoter to be identified. Expression of BRCA1 was significantly up-regulated in AD brains, consistent with its hypomethylation. BRCA1 protein levels were also elevated in response to DNA damage induced by Aβ. BRCA1 became mislocalized to the cytoplasm and highly insoluble in a tau-dependent manner, resulting in DNA fragmentation in both in vitro cellular and in vivo mouse models. BRCA1 dysfunction under Aβ burden is consistent with concomitant deterioration of genomic integrity and synaptic plasticity. The Brca1 promoter region of AD model mice brain was similarly hypomethylated, indicating an epigenetic mechanism underlying BRCA1 regulation in AD. Our results suggest deterioration of DNA integrity as a central contributing factor in AD pathogenesis. Moreover, these data demonstrate the technical feasibility of using neuron-specific DNA methylome analysis to facilitate discovery of etiological candidates in sporadic neurodegenerative diseases.
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影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
4.4
作者：
Bibikova, Marina;Barnes, Bret;Shen, Richard
通讯作者：
Shen, Richard
DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
3.8
作者：
Dedeurwaerder, Sarah;Defrance, Matthieu;Fuks, Francois
通讯作者：
Fuks, Francois
影响因子：
82.9
作者：
Holcomb, L;Gordon, MN;Duff, K
通讯作者：
Duff, K