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, Toru; 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

doi:10.1073/pnas.1707151114

Cited by 79 publications

(65 citation statements)

References 73 publications

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“…In contrast to AD, the number of reads for BMI1 was not significantly different in vascular dementia and mixed-dementia samples ( Figure S1A). Reduced REST, BRCA1, and LRP6 mRNA and/or protein levels were reported in AD brains (Liu et al, 2014;Lu et al, 2014;Mano et al, 2017). However, read numbers for these transcripts were not different between control and AD brains ( Figure S1B).…”

Section: Bmi1 Expression Is Reduced In Ad Brainsmentioning

confidence: 89%

Modeling Late-Onset Sporadic Alzheimer’s Disease through BMI1 Deficiency

et al. 2018

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Late-onset sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but its origin remains poorly understood. The Bmi1/Ring1 protein complex maintains transcriptional repression of developmental genes through histone H2A mono-ubiquitination, and Bmi1 deficiency in mice results in growth retardation, progeria, and neurodegeneration. Here, we demonstrate that BMI1 is silenced in AD brains, but not in those with early-onset familial AD, frontotemporal dementia, or Lewy body dementia. BMI1 expression was also reduced in cortical neurons from AD patient-derived induced pluripotent stem cells but not in neurons overexpressing mutant APP and PSEN1. BMI1 knockout in human post-mitotic neurons resulted in amyloid beta peptide secretion and deposition, p-Tau accumulation, and neurodegeneration. Mechanistically, BMI1 was required to repress microtubule associated protein tau (MAPT) transcription and prevent GSK3beta and p53 stabilization, which otherwise resulted in neurodegeneration. Restoration of BMI1 activity through genetic or pharmaceutical approaches could represent a therapeutic strategy against AD.

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Section: Bmi1 Expression Is Reduced In Ad Brainsmentioning

confidence: 89%

Modeling Late-Onset Sporadic Alzheimer’s Disease through BMI1 Deficiency

et al. 2018

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“…However, when using tissue sample, fixing brain tissue en block has a serious disadvantage in that the surface of the brain may be fixed more than its inside potentially leading to uneven ChIP-seq assay. Given that the separation of neuronal nuclei from non-neuronal ones using FACS is required to achieve specificity in neuronal ChIP-seq 15 , optimization of this step is crucial. Therefore, we tested two different time points for fixing the nucleosome complexes; (1) immediately after homogenization of the frozen brain or (2) after FACS.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, these studies suggest the possibility that epigenetic changes in the neuronal cells were obscured in the bulk analysis and epigenetic analysis using bulk brain can only extract the information that cell-type independent GWAS can identify. On the other hand, neuron-specific DNA methylation analysis of post-mortem brains from Alzheimer's disease patients could help to identify a novel pathomechanism occurring exclusively in neuronal cells 15 . Chromatin accessibility analysis with the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq) in neuronal cells from schizophrenia also provided a novel single nucleotide polymorphism (SNP) with biological relevance 22 .…”

Section: Discussionmentioning

confidence: 99%

Neuron-specific analysis of histone modifications with post-mortem brains

Koshi-Mano

Mano

Morishima

et al. 2020

Sci Rep

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Histone modifications govern chromatin structures and regulate gene expression to orchestrate cellular functions in the central nervous system, where neuronal cells are postmitotic and developmentally inactive, the functional and age-dependent changes also accumulate in the epigenetic states. Because the brain is composed of several types of cells, such as the neurons, glial cells, and vascular cells, the analysis of histone modifications using bulk brain tissue might obscure alterations specific to neuronal cells. Furthermore, among the various epigenetic traits, analysis of the genome-wide distribution of DNA methylation in the bulk brain is predominantly a reflection of DNA methylation of the nonneuronal cells, which may be a potential caveat of previous studies on neurodegenerative diseases using bulk brains. In this study, we established a method of neuron-specific ChIP-seq assay, which allows for the analysis of genome-wide distribution of histone modifications specifically in the neuronal cells derived from post-mortem brains. We successfully enriched neuronal information with high reproducibility and high signal-to-noise ratio. Our method will further facilitate the understanding of neurodegeneration.

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“…In the APP/PSEN1 mouse model for AD, a decrease in the HR protein RAD51 co-exists with DSB accumulation [91]. Additionally, the BRCA1 promoter is hypomethylated and the BRCA1 protein is increased in AD brains; however, the protein was found to be mis-located into the cytoplasm as a highly non-soluble protein through association with tau; BRCA1 in AD brains is thus dysfunctional with respect to DSB repair [92]. This BRCA1 dysfunctionality can be directly induced by Aβ peptides [92].…”

Section: Association Of Hr In Admentioning

confidence: 99%

“…Additionally, the BRCA1 promoter is hypomethylated and the BRCA1 protein is increased in AD brains; however, the protein was found to be mis-located into the cytoplasm as a highly non-soluble protein through association with tau; BRCA1 in AD brains is thus dysfunctional with respect to DSB repair [92]. This BRCA1 dysfunctionality can be directly induced by Aβ peptides [92]. The association of BRCA1 with phosphorylated tau in AD brain was also observed [93], consistent with tau hyperphosphorylation causing tau aggregation.…”

Section: Association Of Hr In Admentioning

confidence: 99%

Contributions of DNA Damage to Alzheimer’s Disease

Lin

Kapoor

et al. 2020

IJMS

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Alzheimer's disease (AD) is the most common type of neurodegenerative disease. Its typical pathology consists of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Mutations in the APP, PSEN1, and PSEN2 genes increase Aβ production and aggregation, and thus cause early onset or familial AD. Even with this strong genetic evidence, recent studies support AD to result from complex etiological alterations. Among them, aging is the strongest risk factor for the vast majority of AD cases: Sporadic late onset AD (LOAD). Accumulation of DNA damage is a well-established aging factor. In this regard, a large amount of evidence reveals DNA damage as a critical pathological cause of AD. Clinically, DNA damage is accumulated in brains of AD patients. Genetically, defects in DNA damage repair resulted from mutations in the BRAC1 and other DNA damage repair genes occur in AD brain and facilitate the pathogenesis. Abnormalities in DNA damage repair can be used as diagnostic biomarkers for AD. In this review, we discuss the association, the causative potential, and the biomarker values of DNA damage in AD pathogenesis.Int. J. Mol. Sci. 2020, 21, 1666 2 of 26 amyloid (senile) plaques in AD brain [9][10][11]. Furthermore, CDK5 activities affect DNA damage response [12], supporting a linkage of DNA damage with AD [13,14].Aβ peptides are directly produced by sequential cleavages of APP by βand γ-secretase; the proteolytic c-terminal fragment of APP (CTFβ) of β-secretase is cleaved within the cell membrane by γ-secretase to generate neurotoxic Aβ peptides with length ranging from 38-43 residues [15][16][17][18][19]. The 40 residue Aβ peptide (Aβ 1-40 ) is the major product, accounting for more than 50% of Aβ peptides [9,17]. Although the Aβ 1-42 peptide consists of less than 10% of Aβ peptides [16,17], it is more neurotoxic and associates with a higher risk of AD because of its propensity of aggregation [9]. The importance of Aβ in AD pathogenesis is illustrated by mutations of APP, PSEN1, and PREN2 genes in familial AD with the latter two encoding the presenilin 1 and presenilin 2 subunit of γ-secretase. Individuals with these mutations develop early onset dementia in an autosomal-dominant manner [20]; the typical onset starts between 30 and 50 years of age in PSEN1 mutant carriers with some being affected at in their 20s [20,21]. γ-secretase with mutant presenilin 1 or presenilin 2 subunit favors Aβ 1-42 production [16,17]. These genetic observations led to formation of the amyloid cascade hypothesis, in which abnormal Aβ drives AD pathogenesis via regulating other pathological events including tau pathology [22][23][24][25][26][27]. This hypothesis is supported by the similar pathological features between familial AD and sporadic late onset AD (LOAD) [20]. Although familial AD constitutes less than 1% of AD cases [28,29], the hypothesis has been widely accepted to guide research in advancing the understanding of both familial AD and LOAD in the past two decades [30,31].Nonetheless, it is becoming in...

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

Cited by 79 publications

References 73 publications

Modeling Late-Onset Sporadic Alzheimer’s Disease through BMI1 Deficiency

Modeling Late-Onset Sporadic Alzheimer’s Disease through BMI1 Deficiency

Neuron-specific analysis of histone modifications with post-mortem brains

Contributions of DNA Damage to Alzheimer’s Disease

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