DNA Methylation of Synaptic Genes in the Prefrontal Cortex Is Associated with Aging and Age-Related Cognitive Impairment

Ianov, Lara; Riva, Alberto; Kumar, Ashok; Foster, Thomas C.

doi:10.3389/fnagi.2017.00249

Cited by 54 publications

(49 citation statements)

References 74 publications

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“…Differential gene body methylation was either positively or negatively correlated to RNA levels in PFC, supporting the idea that DNA methylation is not a strictly repressive mark but it participates of different regulatory mechanisms (Chahrour et al, ; Ianov, Riva et al, ; Penner et al, , ).…”

Section: Dna Methylationsupporting

confidence: 55%

“…In neuronal cells, CpH methylation is enriched in DNA regions showing low CpG‐density. Recent evidences describe important roles for CpH methylation in cognition (Ianov, Riva, Kumar, & Foster, ; Lister et al, ). For example, Guo and colleagues have shown that during neuronal maturation in frontal cortex, highly conserved non‐CpG methylation accumulates to become the dominant form of methylation in the neuronal genome.…”

Section: Dna Methylationmentioning

confidence: 99%

“…With the development of whole genome sequencing, several projects were designed to analyze the entire methylome instead of DNA regions at specific genes. The analysis of rat PFC showed no global changes in the levels of DNA methylation with aging but indicated that DNA methylation is shifted during aging mainly in the gene bodies, where some regions are hypermethylated and others hypomethylated (Ianov, Riva et al, ). Similarly, there was no evidence for a genome‐wide loss methylation in either CpG or CpH sites in hippocampus during aging but over 100.000 CpH sites differentially methylated with aging were also identified in the hippocampus of both males and females (Hadad et al, ; Masser et al, ).…”

Section: Dna Methylationmentioning

confidence: 99%

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Epigenetic mechanisms related to cognitive decline during aging

Harman

Martín

2019

J of Neuroscience Research

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Cognitive decline is a hallmark of the aging nervous system, characterized by increasing memory loss and a deterioration of mental capacity, which in turn creates a favorable context for the development of neurodegenerative diseases. One of the most detrimental alterations that occur at the molecular level in the brain during aging is the modification of the epigenetic mechanisms that control gene expression. As a result of these epigenetic‐driven changes in the transcriptome most of the functions of the brain including synaptic plasticity, learning, and memory decline with aging. The epigenetic mechanisms altered during aging include DNA methylation, histone modifications, nucleosome remodeling, and microRNA‐mediated gene regulation. In this review, we examine the current evidence concerning the changes of epigenetic modifications together with the molecular mechanisms underlying impaired neuronal gene transcription during aging. Herein, we discuss the alterations of DNA methylation pattern that occur in old neurons. We will also describe the most prominent age‐related histone posttranslational modifications in the brain since changes in acetylation and methylation of specific lysine residues on H3 and H4 are associated to functional decline in the old. In addition, we discuss the role that changes in the levels of certain miRNAs would play in cognitive decline with aging. Finally, we provide an overview about the mechanisms either extrinsic or intrinsic that would trigger epigenetic changes in the aging brain, and the consequences of these changes, i.e., altered transcriptional profile and reactivation of transposable elements in old brain.

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Section: Dna Methylationsupporting

confidence: 55%

Section: Dna Methylationmentioning

confidence: 99%

Section: Dna Methylationmentioning

confidence: 99%

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Epigenetic mechanisms related to cognitive decline during aging

Harman

Martín

2019

J of Neuroscience Research

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“…[63][64][65][66] One major group of pathways that emerged from our methylome analysis following neonatal inflammation-induced WMI was related to the axon. 72 Thus, the hypermethylation of genes related to axonal compartment, seen in our study, could reflect the onset of long-lasting changes in neurodevelopment. 38,40 Furthermore, using the microtubule-associated protein 1 expressed in axons, Fan et al have confirmed that axonal fragmentation, already present 3 days after LPS exposure, was still there 70 days later.…”

Section: F I G U R E 4 Methylation Levels Of Genes Of Interest Associmentioning

confidence: 50%

Alteration of the brain methylation landscape following postnatal inflammatory injury in rat pups

et al. 2019

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This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. contributed equally to this study.Abbreviations: ASD, autism spectrum disorder; CpG, cytosine followed by guanine; DMR, differentially methylated region; DOHaD, developmental origins of health and disease; E. coli, Escherichia coli; GO, gene ontology; LPS, lipopolysaccharide; P3, postnatal day 3; P4, postnatal day 4; P24, postnatal day 24; PBS, phosphate-buffered saline; PFA, paraformaldehyde; RRBS, reduced representation bisulfite sequencing; WMI, white matter injury. AbstractPreterm infants are vulnerable to inflammation-induced white matter injury (WMI), which is associated with neurocognitive impairment and increased risk of neuropsychiatric diseases in adulthood. Epigenetic mechanisms, particularly DNA methylation, play a role in normal development and modulate the response to pathological challenges. Our aims were to determine how WMI triggered DNA methylation alterations in brains of neonatal rats and if such changes persisted over time. We used a robust model of WMI by injecting lipopolysaccharide (LPS) or sterile saline in the corpus callosum of 3-day-old (P3) rat pups. Brains were collected 24 hours (P4) and 21 days post-injection (P24). We extracted genomic DNA from the brain to establish genome-wide quantitative DNA methylation profiles using reduced representation bisulfite sequencing. Neonatal LPS exposure induced a persistent increased methylation of genes related to nervous system development and a reduced methylation of genes associated with inflammatory pathways. These findings suggest that early-life neuroinflammatory exposure impacts the cerebral methylation landscape with determining widespread epigenetic modifications especially in genes related to neurodevelopment. K E Y W O R D SDNA methylation, epigenetics, lipopolysaccharide, periventricular leukomalacia

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“…The GO and KEGG enrichment analysis for the probes in the 'yellowgreen' module highlighted many pathways associated with the pathophysiology of cognitive dysfunction and dementia (Supplementary Tables 4 & 5), for example, the GO terms 'main axon' (GO:0044304: p = 4.37E-03) and 'β-amyloid binding' (GO:0001540: p = 0.0109), and the KEGG pathways 'glutamatergic synapse' (hsa04727: p = 4.79E-04) and 'Alzheimer's disease' (hsa05010: p = 0.0491). DNAm and hydroxymethylation changes in genes involved in these pathways, such as axon and glutamatergic synapse have been previously linked to brain aging and cognition in experimental models [44,45].…”

Section: Accelerated Blood Dnam Age Is Associated With Mri Alterationsmentioning

confidence: 99%

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

et al. 2018

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Aim:The present study investigated the link between peripheral DNA methylation (DNAm), cognitive impairment and brain aging. Methods: We tested the association between blood genome-wide DNAm profiles using the Illumina 450K arrays, cognitive dysfunction and brain MRI measures in selected participants of the Whitehall II imaging sub-study. Results: Eight differentially methylated regions were associated with cognitive impairment. Accelerated aging based on the Hannum epigenetic clock was associated with mean diffusivity and global fractional anisotropy. We also identified modules of co-methylated loci associated with white matter hyperintensities. These co-methylation modules were enriched among pathways relevant to β-amyloid processing and glutamatergic signaling. Conclusion: Our data support the notion that blood DNAm changes may have utility as a biomarker for cognitive dysfunction and brain aging. DNA methylation (DNAm) changes have been linked with the pathophysiology of brain aging, Alzheimer's disease (AD) and other types of dementia [1,2]. Considering the relative stability of DNAm and the fact that it is directly modulated by both underlying genetic sequence and environmental exposures it appears as a promising peripheral biomarker for brain-related changes [3]. Peripheral changes in mRNA and proteins that are downstream of DNAm regulation further support this concept [4,5]. Studies have shown differences in blood DNAm when comparing AD subjects with controls [6], but interestingly when looking at specific genes there is little overlap between brain and blood DNAm changes in AD [7,8]. However, a good peripheral biomarker does not have to mirror disease-associated changes in the brain; it could also simply represent a peripheral response to central pathology. At present, there is limited data available on the potential utility of peripheral DNAm as a marker for cognitive decline before the onset of dementia. One study of patients with Type 2 diabetes mellitus who later developed presymptomatic dementia highlighted leukocyte DNAm changes that were comparable to changes identified in blood in AD patients and could thus potentially represent early markers of dementia [9]. Recently DNAm epigenetic clocks have been developed, which provide a measure of epigenetic age, based on DNAm levels at 353 CpG sites [10] and 71 CpG sites [11], respectively. A number of studies have utilized the epigenetic age in blood, based on the DNAm epigenetic clock, to show correlations with cognitive function, white matter hyperintensities (WMH), Parkinson's disease, Down syndrome and all-cause mortality [12][13][14][15][16].

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DNA Methylation of Synaptic Genes in the Prefrontal Cortex Is Associated with Aging and Age-Related Cognitive Impairment

Cited by 54 publications

References 74 publications

Epigenetic mechanisms related to cognitive decline during aging

Epigenetic mechanisms related to cognitive decline during aging

Alteration of the brain methylation landscape following postnatal inflammatory injury in rat pups

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

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