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

Tatsuo Mano, Kenichi Nagata, Takashi Nonaka, Airi Tarutani, Tomohiro Imamura, Tadafumi Hashimoto, Taro Bannai, Kagari Koshi-Mano, Takeyuki Tsuchida, Ryo Ohtomo, Junko Takahashi-Fujigasaki, Satoshi Yamashita, Yasumasa Ohyagi, Ryo Yamasaki, Shoji Tsuji, Akira Tamaoka, Takeshi Ikeuchi, Takaomi C. Saido, Takeshi Iwatsubo, Toshikazu Ushijima & 3 others Shigeo Murayama, Masato Hasegawa, Atsushi Iwata

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)E9645-E9654
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number45
DOIs
Publication statusPublished - Nov 7 2017

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Epigenomics
Alzheimer Disease
Neurons
Brain
Genetic Promoter Regions
Neurodegenerative Diseases
DNA
BRCA1 Protein
tau Proteins
Neuronal Plasticity
DNA Fragmentation
Amyloid
DNA Damage
Cytoplasm
Chronic Disease
Pathology

All Science Journal Classification (ASJC) codes

  • General

Cite this

Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer’s disease. / Mano, Tatsuo; Nagata, Kenichi; Nonaka, Takashi; Tarutani, Airi; Imamura, Tomohiro; Hashimoto, Tadafumi; Bannai, Taro; Koshi-Mano, Kagari; Tsuchida, Takeyuki; Ohtomo, Ryo; Takahashi-Fujigasaki, Junko; Yamashita, Satoshi; Ohyagi, Yasumasa; Yamasaki, Ryo; Tsuji, Shoji; Tamaoka, Akira; Ikeuchi, Takeshi; Saido, Takaomi C.; Iwatsubo, Takeshi; Ushijima, Toshikazu; Murayama, Shigeo; Hasegawa, Masato; Iwata, Atsushi.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 45, 07.11.2017, p. E9645-E9654.

Research output: Contribution to journalArticle

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 2017, 'Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer’s disease', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 45, pp. E9645-E9654. https://doi.org/10.1073/pnas.1707151114
Mano, Tatsuo ; Nagata, Kenichi ; Nonaka, Takashi ; Tarutani, Airi ; Imamura, Tomohiro ; Hashimoto, Tadafumi ; Bannai, Taro ; Koshi-Mano, Kagari ; Tsuchida, Takeyuki ; Ohtomo, Ryo ; Takahashi-Fujigasaki, Junko ; Yamashita, Satoshi ; Ohyagi, Yasumasa ; Yamasaki, Ryo ; Tsuji, Shoji ; Tamaoka, Akira ; Ikeuchi, Takeshi ; Saido, Takaomi C. ; Iwatsubo, Takeshi ; Ushijima, Toshikazu ; Murayama, Shigeo ; Hasegawa, Masato ; Iwata, Atsushi. / Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer’s disease. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 45. pp. E9645-E9654.
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AU - Nagata, Kenichi

AU - Nonaka, Takashi

AU - Tarutani, Airi

AU - Imamura, Tomohiro

AU - Hashimoto, Tadafumi

AU - Bannai, Taro

AU - Koshi-Mano, Kagari

AU - Tsuchida, Takeyuki

AU - Ohtomo, Ryo

AU - Takahashi-Fujigasaki, Junko

AU - Yamashita, Satoshi

AU - Ohyagi, Yasumasa

AU - Yamasaki, Ryo

AU - Tsuji, Shoji

AU - Tamaoka, Akira

AU - Ikeuchi, Takeshi

AU - Saido, Takaomi C.

AU - Iwatsubo, Takeshi

AU - Ushijima, Toshikazu

AU - Murayama, Shigeo

AU - Hasegawa, Masato

AU - Iwata, Atsushi

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N2 - 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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