Epigenetic signatures of methylated DNA cytosine in Alzheimer’s disease

Fetahu, Irfete S.; Ma, Dingailu; Rabidou, Kimberlie; Argueta, Christian; Smith, M. R.; Liu, Huan; Wu, Feizhen; Shi, Yujiang Geno

doi:10.1126/sciadv.aaw2880

Cited by 44 publications

(42 citation statements)

References 43 publications

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“…On the other hand, epigenetic factors, such as adverse environmental cues or aging, may directly reprogram the epigenome, which, in turn, may alter the expression-associated genes to result in neurodegenerative diseases [76]. In our previous study [17], we reported the first genome-wide roadmap of epigenetic signatures in AD based on the methylated DNA base cytosine [17]. Significantly, in the present study, we determined novel FUS-specific AD genes, whose transcriptional alterations were significantly linked to key AD risk factors.…”

Section: Discussionmentioning

confidence: 86%

“…Oxidative (oxBS-seq) and methylase-assisted bisulfite sequencing (MAB-seq) at single-base-pair resolution were performed as previously described [17]. We performed oxBS-seq and MAB-seq in all cell lines in the AD patient samples reported in this study.…”

Section: Oxidative and Methylase-assisted Bisulfite Sequencingmentioning

confidence: 99%

“…We evaluated the data quality of oxBS-seq and MAB-seq [17] and used the bsmap (v2.74) [78] software package to align the reads to the human reference genome of UCSC (hg19) and to identify the methylation signals. We retained CpG sites with a sequencing depth of at least 10× for downstream analysis.…”

Section: Identification Of 5mc 5hmc and 5fc/5cac Sitesmentioning

confidence: 99%

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The fusiform gyrus exhibits an epigenetic signature for Alzheimer’s disease

Fetahu

Wang

et al. 2020

Clin Epigenet

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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.

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Section: Discussionmentioning

confidence: 86%

Section: Oxidative and Methylase-assisted Bisulfite Sequencingmentioning

confidence: 99%

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The fusiform gyrus exhibits an epigenetic signature for Alzheimer’s disease

Fetahu

Wang

et al. 2020

Clin Epigenet

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“…Several studies support the idea that dysregulated DNA methylation/demethylation is linked to many neuronal disorders, including AD onset and progression. However, the relationship between AD and altered 5-mC levels is not known [37]. 5-mC can be further oxidized to 5-hmC, among others, by the TET family of dioxygenases.…”

Section: Discussionmentioning

confidence: 99%

Chronic Mild Stress Modified Epigenetic Mechanisms Leading to Accelerated Senescence and Impaired Cognitive Performance in Mice

Puigoriol-Illamola

Martínez-Damas

Pallàs

2020

IJMS

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Cognitive and behavioural disturbances are a growing public healthcare issue for the modern society, as stressful lifestyle is becoming more and more common. Besides, several pieces of evidence state that environment is crucial in the development of several diseases as well as compromising healthy aging. Therefore, it is important to study the effects of stress on cognition and its relationship with aging. To address these queries, Chronic Mild Stress (CMS) paradigm was used in the senescence-accelerated mouse prone 8 (SAMP8) and resistant 1 (SAMR1). On one hand, we determined the changes produced in the three main epigenetic marks after 4 weeks of CMS treatment, such as a reduction in histone posttranslational modifications and DNA methylation, and up-regulation or down-regulation of several miRNA involved in different cellular processes in mice. In addition, CMS treatment induced reactive oxygen species (ROS) damage accumulation and loss of antioxidant defence mechanisms, as well as inflammatory signalling activation through NF-κB pathway and astrogliosis markers, like Gfap. Remarkably, CMS altered mTORC1 signalling in both strains, decreasing autophagy only in SAMR1 mice. We found a decrease in glycogen synthase kinase 3 β (GSK-3β) inactivation, hyperphosphorylation of Tau and an increase in sAPPβ protein levels in mice under CMS. Moreover, reduction in the non-amyloidogenic secretase ADAM10 protein levels was found in SAMR1 CMS group. Consequently, detrimental effects on behaviour and cognitive performance were detected in CMS treated mice, affecting mainly SAMR1 mice, promoting a turning to SAMP8 phenotype. In conclusion, CMS is a feasible intervention to understand the influence of stress on epigenetic mechanisms underlying cognition and accelerating senescence.responses to different stimulus [1]. Indeed, normal aging differs from pathological aging and this might be explained by the lifestyle. Environmental factors drive epigenetic modifications, resulting in phenotypic differences, which alter almost all tissues and organs. Although the brain is one of the most affected structures, such modifications lead to a progressive decline in the cognitive function and create a favourable context for the development of neurodegenerative diseases [2]. Aging is the most significant risk factor for most chronic diseases, such as age-related cognitive decline and Alzheimer's disease (AD) [3]. In fact, AD is the most prevalent dementia and its progression is influenced by both genetic and environmental factors [4].Several studies define that a good environment is essential to enhance learning and cognitive abilities, besides the continued presence of stressors being associated with the opposite effects. Epigenetics refers to potentially heritable and environmentally modifiable changes in gene expression mediated via non-DNA encoded mechanisms [5]. Recent evidence has demonstrated significant associations between epigenetic alterations and stress [2,6]. Potential threats cause a course of action releasing numerous transm...

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“…It is well known that DNA methylation at the fifth position of cytosine (5-mC) plays an important role in neuronal gene expression and neural development. Several studies support the idea that dysregulated DNA methylation/demethylation is linked to many neuronal disorders, including AD onset and progression; however, the relationship between AD and altered 5-mC levels is not known [40]. 5-mC can be further oxidized to 5-hmC, among others, by the TET family of dioxygenases.…”

Section: Discussionmentioning

confidence: 99%

Chronic Mild Stress Modified Epigenetic Mechanisms Leading to Accelerated Senescence and Impaired Cognitive Performance in Mice

Puigoriol-Illamola¹,

Martínez-Damas²,

Griñán-Ferré³

et al. 2020

Preprint

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Cognitive and behavioural disturbances are growing public healthcare issue for the modern society, as stressful lifestyle is becoming more and more common. Besides, several pieces of evidence state that environment is crucial in the development of several diseases as well as compromising healthy aging. Therefore, it is important to study the effects of stress on cognition and its relationship with aging. To address these queries, Chronic Mild Stress (CMS) paradigm was used in the senescence-accelerated mouse prone 8 (SAMP8) and resistant 1 (SAMR1). On one hand, we determined the changes produced in the three main epigenetic marks after 4 weeks of CMS treatment, such as a reduction in histone posttranslational modifications and DNA methylation, and up-regulation or down-regulation of several miRNA involved in different cellular processes in mice. In addition, CMS treatment induced reactive oxygen species (ROS) accumulation and loss of antioxidant defence mechanisms, as well as inflammatory signalling activation through NF-κB pathway and astrogliosis markers, like Gfap. Remarkably, CMS altered mTORC1 signalling in both strains, decreasing autophagy only in SAMR1 mice. We found a decrease in glycogen synthase kinase 3 β (GSK-3β) inactivation, hyperphosphorylation of Tau and an increase in sAPPβ protein levels in mice under CMS. Moreover, reduction in the non-amyloidogenic secretase ADAM10 protein levels was found in SAMR1 CMS group. Consequently, detrimental effects on behaviour and cognitive performance were detected in CMS treated mice, affecting mainly SAMR1 mice, promoting a turning to SAMP8 phenotype. In conclusion, CMS is a feasible intervention to understand the influence of stress on epigenetic mechanisms underlying cognition and accelerating senescence.

show abstract

Epigenetic signatures of methylated DNA cytosine in Alzheimer’s disease

Cited by 44 publications

References 43 publications

The fusiform gyrus exhibits an epigenetic signature for Alzheimer’s disease

The fusiform gyrus exhibits an epigenetic signature for Alzheimer’s disease

Chronic Mild Stress Modified Epigenetic Mechanisms Leading to Accelerated Senescence and Impaired Cognitive Performance in Mice

Chronic Mild Stress Modified Epigenetic Mechanisms Leading to Accelerated Senescence and Impaired Cognitive Performance in Mice

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