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Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid ? (A?) 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 A?. 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 A? 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.

SUBMITTER: Mano T

PROVIDER: S-EPMC5692545 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease.

Mano Tatsuo T Nagata Kenichi K Nonaka Takashi T Tarutani Airi A Imamura Tomohiro T Hashimoto Tadafumi T Bannai Taro T Koshi-Mano Kagari K Tsuchida Takeyuki T Ohtomo Ryo R Takahashi-Fujigasaki Junko J Yamashita Satoshi S Ohyagi Yasumasa Y Yamasaki Ryo R Tsuji Shoji S Tamaoka Akira A Ikeuchi Takeshi T Saido Takaomi C TC Iwatsubo Takeshi T Ushijima Toshikazu T Murayama Shigeo S Hasegawa Masato M Iwata Atsushi A

Proceedings of the National Academy of Sciences of the United States of America 20171017 45

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 ...[more]

PMID: 29042514

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Project description:BackgroundAtherosclerotic plaque vulnerability is a key feature of atheroprogression and precipitating acute cardiovascular events. Although the pivotal role of epigenetic regulation in atherosclerotic plaque destabilization is being recognized, the DNA methylation profile and its potential role in driving the progression and destabilization of atherosclerotic cardiovascular disease remains largely unknown. We conducted a genome-wide analysis to identify differentially methylated genes in vulnerable and non-vulnerable atherosclerotic lesions to understand more about pathogenesis.ResultsWe compared genome-wide DNA methylation profiling between carotid artery plaques of patients with clinically symptomatic (recent stroke or transient ischemic attack) and asymptomatic disease (no recent stroke) using Infinium Methylation BeadChip arrays, which revealed 90,368 differentially methylated sites (FDR < 0.05, |delta beta|> 0.03) corresponding to 14,657 annotated genes. Among these genomic sites, 30% were located at the promoter regions and 14% in the CpG islands, according to genomic loci and genomic proximity to the CpG islands, respectively. Moreover, 67% displayed hypomethylation in symptomatic plaques, and the differentially hypomethylated genes were found to be involved in various aspects of inflammation. Subsequently, we focus on CpG islands and revealed 14,596 differentially methylated sites (|delta beta|> 0.1) located at the promoter regions of 7048 genes. Integrated analysis of methylation and gene expression profiles identified that 107 genes were hypomethylated in symptomatic plaques and showed elevated expression levels in both advanced plaques and ruptured plaques. The imprinted gene PLA2G7, which encodes lipoprotein-associated phospholipase A2 (Lp-PLA2), was one of the top hypomethylated genes with an increased expression upon inflammation. Further, the hypomethylated CpG site at the promoter region of PLA2G7 was identified as cg11874627, demethylation of which led to increased binding of Sp3 and expression of Lp-PLA2 through bisulfate sequencing, chromatin immunoprecipitation assay and enzyme-linked immunosorbent assay. These effects were further enhanced by deacetylase.ConclusionExtensive DNA methylation modifications serve as a new and critical layer of biological regulation that contributes to atheroprogression and destabilization via inflammatory processes. Revelation of this hitherto unknown epigenetic regulatory mechanism could rejuvenate the prospects of Lp-PLA2 as a therapeutic target to stabilize the atherosclerotic plaque and reduce clinical sequelae.

Dataset Information

Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease.

Publications

Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease.

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