PMCID: PMC3454416This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Corey T. Watson

Felix Breden

Gavin Giovannoni

Geir Kjetil Sandve

Giulio Disanto

Sreeram V. Ramagopalan

Wolfgang Wagner

PLoS ONE

English

PubMed

Recent associations between age-related differentially methylated sites and bivalently marked chromatin domains have implicated a role for these genomic regions in aging and age-related diseases. However, the overlap between such epigenetic modifications has so far only been identified with respect to age-associated hyper-methylated sites in blood. In this study, we observed that age-associated differentially methylated sites characterized in the human brain were also highly enriched in bivalent domains. Analysis of hyper- vs. hypo-methylated sites partitioned by age (fetal, child, and adult) revealed that enrichment was significant for hyper-methylated sites identified in children and adults (child, fold difference = 2.28, P = 0.0016; adult, fold difference = 4.73, P = 4.00×10−5); this trend was markedly more pronounced in adults when only the top 100 most significantly hypo- and hyper-methylated sites were considered (adult, fold difference = 10.7, P = 2.00×10−5). Interestingly, we found that bivalently marked genes overlapped by age-associated hyper-methylation in the adult brain had strong involvement in biological functions related to developmental processes, including neuronal differentiation. Our findings provide evidence that the accumulation of methylation in bivalent gene regions with age is likely to be a common process that occurs across tissue types. Furthermore, particularly with respect to the aging brain, this accumulation might be targeted to loci with important roles in cell differentiation and development, and the closing off of these developmental pathways. Further study of these genes is warranted to assess their potential impact upon the development of age-related neurological disorders

Watson, Corey T.

Disanto, Giulio

Sandve, Geir Kjetil

Breden, Felix

Giovannoni, Gavin

Ramagopalan, Sreeram V.

Simon Fraser University Institutional Repository

Age-Associated Hyper-Methylated Regions in the Human Brain Overlap with Bivalent Chromatin Domains

Watson, Corey

Sandve, Geir

Recent associations between age-related differentially methylated sites and bivalently marked chromatin domains have implicated a role for these genomic regions in aging and age-related diseases. However, the overlap between such epigenetic modifications has so far only been identified with respect to age-associated hyper-methylated sites in blood. In this study, we observed that age-associated differentially methylated sites characterized in the human brain were also highly enriched in bivalent domains. Analysis of hyper- vs. hypo-methylated sites partitioned by age (fetal, child, and adult) revealed that enrichment was significant for hyper-methylated sites identified in children and adults (child, fold difference = 2.28, P = 0.0016; adult, fold difference = 4.73, P = 4.00 × 10(-5)); this trend was markedly more pronounced in adults when only the top 100 most significantly hypo- and hyper-methylated sites were considered (adult, fold difference = 10.7, P = 2.00 × 10(-5)). Interestingly, we found that bivalently marked genes overlapped by age-associated hyper-methylation in the adult brain had strong involvement in biological functions related to developmental processes, including neuronal differentiation. Our findings provide evidence that the accumulation of methylation in bivalent gene regions with age is likely to be a common process that occurs across tissue types. Furthermore, particularly with respect to the aging brain, this accumulation might be targeted to loci with important roles in cell differentiation and development, and the closing off of these developmental pathways. Further study of these genes is warranted to assess their potential impact upon the development of age-related neurological disorders

Corey T Watson

Sreeram V Ramagopalan

Directory of Open Access Journals

Age-associated hyper-methylated regions in the human brain overlap with bivalent chromatin domains.

Watson Corey T.

Disanto Giulio

Sandve Geir Kjetil

Breden Felix

Giovannoni Gavin

Ramagopalan Sreeram V.

Public Library of Science (PLOS)

Crossref

Watson, CT

Disanto, G

Sandve, GK

Breden, F

Giovannoni, G

Ramagopalan, SV

Queen Mary Research Online

A bivalent chromatin structure marks key developmental genes in embryonic stem cells.

Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer.

Ageassociated DNA methylation in pediatric populations.

Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS

Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists.

Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus.

Chromatin signatures of pluripotent cell lines.

Distinct DNA methylation changes highly correlated with chronological age in the human brain.

DNA methylation signatures in development and aging of the human prefrontal cortex.

Epigenetic differences arise during the lifetime of monozygotic twins.

Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer’s disease.

Genomescale DNA methylation maps of pluripotent and differentiated cells.

Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains.

Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum Mol Genet

Neuroregeneration in neurodegenerative disorders.

Specific ageassociated DNA methylation changes in human dermal fibroblasts.

Stem cell chromatin patterns: an instructive mechanism for DNA hypermethylation?

Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.

The Genomic HyperBrowser: inferential genomics at the sequence level.

Whole-genome mapping of histone H3

Widespread and tissue specific age-related DNA methylation changes in mice.

Oxford University Research Archive (ORA)

Age-associated hyper-methylated regions in the human brain overlap with bivalent chromatin domains

file:///data/remote/core/dit/data/public_library_of_science/pdf/c3d/ZnRwOi8vZnRwLm5jYmkubmxtLm5paC5nb3YvcHViL3BtYy9vYV9wYWNrYWdlLzYzL2Y5L1BNQzM0NTQ0MTYudGFyLmd6.pdf

Age-Associated Hyper-Methylated Regions in the Human Brain Overlap with Bivalent Chromatin Domains

Abstract

Similar works

Full text

Available Versions

Simon Fraser University Institutional Repository

Simon Fraser University Institutional Repository

Directory of Open Access Journals

Public Library of Science (PLOS)

Crossref

Queen Mary Research Online

Oxford University Research Archive (ORA)

Public Library of Science (PLOS)