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Inactive or moderately active human promoters are enriched for inter-individual epialleles

Title: Inactive or moderately active human promoters are enriched for inter-individual epialleles
Author(s): Gemma, C
Ramagopalan, SV
Down, TA
Beyan, H
Hawa, MI
Holland, ML
Hurd, PJ
Giovannoni, G
Leslie, RD
Ebers, GC
Rakyan, VK
Item Type: Journal Article
Abstract: BACKGROUND: Inter-individual epigenetic variation, due to genetic, environmental or random influences, is observed in many eukaryotic species. In mammals, however, the molecular nature of epiallelic variation has been poorly defined, partly due to the restricted focus on DNA methylation. Here we report the first genome-scale investigation of mammalian epialleles that integrates genomic, methylomic, transcriptomic and histone state information. RESULTS: First, in a small sample set, we demonstrate that non-genetically determined inter-individual differentially methylated regions (iiDMRs) can be temporally stable over at least 2 years. Then, we show that iiDMRs are associated with changes in chromatin state as measured by inter-individual differences in histone variant H2A.Z levels. However, the correlation of promoter iiDMRs with gene expression is negligible and not improved by integrating H2A.Z information. We find that most promoter epialleles, whether genetically or non-genetically determined, are associated with low levels of transcriptional activity, depleted for housekeeping genes, and either depleted for H3K4me3/enriched for H3K27me3 or lacking both these marks in human embryonic stem cells. The preferential enrichment of iiDMRs at regions of relative transcriptional inactivity validates in a larger independent cohort, and is reminiscent of observations previously made for promoters that undergo hypermethylation in various cancers, in vitro cell culture and ageing. CONCLUSIONS: Our work identifies potential key features of epiallelic variation in humans, including temporal stability of non-genetically determined epialleles, and concomitant perturbations of chromatin state. Furthermore, our work suggests a novel mechanistic link among inter-individual epialleles observed in the context of normal variation, cancer and ageing.
Publication Date: 25-May-2013
Date of Acceptance: 25-May-2013
URI: http://hdl.handle.net/10044/1/34422
DOI: http://dx.doi.org/10.1186/gb-2013-14-5-r43
ISSN: 1474-760X
Publisher: BioMed Central
Journal / Book Title: Genome Biology
Volume: 14
Copyright Statement: © Gemma et al. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Alleles
DNA Methylation
Embryonic Stem Cells
Epigenesis, Genetic
Female
Gene Expression Regulation
Genome, Human
Genomics
Histones
Humans
Molecular Sequence Data
Promoter Regions, Genetic
Twins, Monozygotic
Humans
Histones
Genomics
DNA Methylation
Gene Expression Regulation
Epigenesis, Genetic
Twins, Monozygotic
Alleles
Genome, Human
Molecular Sequence Data
Female
Embryonic Stem Cells
Promoter Regions, Genetic
Bioinformatics
05 Environmental Sciences
06 Biological Sciences
08 Information And Computing Sciences
Publication Status: Published
Article Number: R43
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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