Abstract
BackgroundInter-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.ResultsFirst, 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.ConclusionsOur 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.
Highlights
Inter-individual epigenetic variation, due to genetic, environmental or random influences, is observed in many eukaryotic species
Using a combination of experimental and computational analyses we identify key features of epiallelic variation in humans, including demonstrating that even non-genetically determined epialleles can be temporally stable, and that DNA methylation variability at epialleles is associated with concomitant perturbations in chromatin state
We focussed on CD14+ cells as they can be obtained to >90% purity [17] and Additional file 1, Figure S1, and are less likely to harbor post-differentiation, random epigenetic alterations as they have a lifespan of only a few weeks
Summary
Inter-individual epigenetic variation, due to genetic, environmental or random influences, is observed in many eukaryotic species. The molecular nature of epiallelic variation has been poorly defined, partly due to the restricted focus on DNA methylation. (2) exposure to a compromised in utero environment as has been shown in rodent and human studies [10,11,12]; (3) or adult life-style associated factors such as smoking [13]. Despite these and other previous studies, the molecular nature of mammalian epialleles, in particular those induced by non-genetic factors, has remained controversial [14]. Incorporation of information about the chromatin state would refine our understanding of the molecular nature and functionality of epialleles in the context of normal variation or disease states
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
