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Open Access Research

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

Carolina Gemma1, Sreeram V Ramagopalan12*, Thomas A Down3, Huriya Beyan1, Mohammed I Hawa1, Michelle L Holland1, Paul J Hurd4, Gavin Giovannoni1, R David Leslie1, George C Ebers5 and Vardhman K Rakyan1*

Author Affiliations

1 The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK

2 Department of Physiology, Anatomy and Genetics and Medical Research Council Functional Genomics Unit, South Parks Road, Oxford, OX1 3PT, UK

3 The Gurdon Institute and Department of Genetics, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK

4 School of Biological and Chemical Sciences, Queen Mary University of London, London, E1 4NS, UK

5 Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford OX3 7BN, UK

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Genome Biology 2013, 14:R43  doi:10.1186/gb-2013-14-5-r43

Published: 25 May 2013

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.

Keywords:
Epigenetics; DNA methylation; epialleles