Opening up the DNA methylome of dementia

Delgado-Morales, Raúl; Esteller, Manel

doi:10.1038/mp.2016.242

Cited by 56 publications

(40 citation statements)

References 180 publications

(229 reference statements)

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“…Epigenetics study heritable alterations in gene expression that happens without any change of the DNA sequence, linking the genome with the surrounding environment [2][3][4]. It has been well established that the accumulation of different epigenetic alterations over the lifespan might contribute to neurodegenerative and cerebrovascular disorders and that neuroepigenetics plays a crucial role in neurodegenerative processes [5][6][7]. DNA methylation is the most investigated epigenetic hallmark.…”

Section: Introductionmentioning

confidence: 99%

DNA Methylation in Neurodegenerative and Cerebrovascular Disorders

Martínez-Iglesias

Carrera

Carril

et al. 2020

IJMS

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DNA methylation is an epigenetic mechanism by which methyl groups are added to DNA, playing a crucial role in gene expression regulation. The aim of the present study is to compare methylation status of healthy subjects with that of patients with Alzheimer’s, Parkinson’s or Cerebrovascular diseases. We also analyze methylation status of a transgenic Alzheimer’s disease mouse model (3xTg-AD). Our results show that both global methylation (n = 141) and hydroxymethylation (n = 131) levels are reduced in DNA samples from buffy coats of patients with neurodegenerative disorders and age-related cerebrovascular disease. The importance of methylation and hydroxymethylation reduction is stressed by the finding that DNMT3a mRNA levels are also downregulated in buffy coats of patients with Dementia (n = 25). Global methylation is also reduced in brain, liver and serum samples of 3xTg-AD vs. wild type mice, such as DNMT3a mRNA levels that are also decreased in the brain of 3xTg-AD (n = 10). These results suggest that the use of global methylation and hydroxymethylation levels, together with the study of DNMT3a expression, could be useful as a new diagnostic biomarker for these prevalent disorders.

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Section: Introductionmentioning

confidence: 99%

DNA Methylation in Neurodegenerative and Cerebrovascular Disorders

Martínez-Iglesias

Carrera

Carril

et al. 2020

IJMS

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“…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].…”

mentioning

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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“…They vary across individuals and this variation has been robustly associated with a range of disease phenotypes and environmental exposures [1][2][3][4][5][6]. As interindividual DNA methylation is specified by the interaction of both genotypic and environmental influences [7,8], it may be a more powerful prognostic biomarker than either genotypic or lifestyle factors alone [9].…”

Section: Dna Methylation Marks Integrate Genetic and Environmental Inflmentioning

confidence: 99%

Is Cellular Heterogeneity Merely a Confounder to be Removed from Epigenome-Wide Association Studies?

et al. 2017

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Excitement about DNA methylation biomarkers has been tempered by a growing appreciation of the complex causal relations with cell fate. Intersample differences in DNA methylation can be partitioned into those that are independent of cellular heterogeneity and those that are caused by differential mixtures of cell types. Generally, the field has assumed that the former are more likely to be causative of disease. The latter has been considered a likely consequence of disease and a confounder to be removed. We argue that the conceptual separation of these signals is artificial and not necessarily informative about causation. DNA methylation is a very sensitive measure of cell fate mix and therefore reveals much about underlying disease etiology including aspects of causation. DNA methylation marks integrate genetic & environmental influences & hence have potential as prognostic & stratification biomarkers & also as read-outs of intervention efficacyLoci-specific DNA 5-methylcytosine levels at CpG sites are easily measured at scale in biological samples. They vary across individuals and this variation has been robustly associated with a range of disease phenotypes and environmental exposures [1][2][3][4][5][6]. As interindividual DNA methylation is specified by the interaction of both genotypic and environmental influences [7,8], it may be a more powerful prognostic biomarker than either genotypic or lifestyle factors alone [9]. DNA methylation is dynamic throughout the lifecourse and is potentially modifiable by therapeutic interventions. This raises the possibility of sensitive real-time biomarkers of disease status to track intervention efficacy [10].Locus-specific observations were first to demonstrate the role of early life environmental influence on interindividual variation in methylation. For instance, postnatal maternal care in rats or childhood trauma in humans, affects DNA methylation levels at the NR3C1 gene in blood and the hippocampus; methylation levels at this locus then predict adult psychopathology [11][12][13]. Observations such as this have inspired many epigenome wide association studies (EWAS) to determine the epigenetic consequences of early life influences. Although epigenetic programming was originally envisioned to pertain to very early life factors (i.e., fetal programming, see for example [14]), it could be generalized to account for environmental influences throughout the lifecourse. Some of the best evidence for the later life effect of the environment on DNA methylation is from Fasanelli and colleagues, who showed (by EWAS) that smoking reversibly caused hypomethylation of the AHRR and FR2L3 genes in adults and that

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Opening up the DNA methylome of dementia

Cited by 56 publications

References 180 publications

DNA Methylation in Neurodegenerative and Cerebrovascular Disorders

DNA Methylation in Neurodegenerative and Cerebrovascular Disorders

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

Is Cellular Heterogeneity Merely a Confounder to be Removed from Epigenome-Wide Association Studies?

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