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Developing andevaluating complexinterventions: thenew Medical ResearchCouncil guidance Peter CraigPaul DieppeSally MacIntyre2008 год

Developing and evaluating complex interventions: the new Medical Research Council guidance
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Abstract

DNA methylation is an important epigenetic regulator of gene expression. Recent studies have revealed widespread associations between genetic variation and methylation levels. However, the mechanistic links between genetic variation and methylation remain unclear. To begin addressing this gap, we collected methylation data at ∼300,000 loci in lymphoblastoid cell lines (LCLs) from 64 HapMap Yoruba individuals, and genome-wide bisulfite sequence data in ten of these individuals. We identified (at an FDR of 10%) 13,915 cis methylation QTLs (meQTLs)—i.e., CpG sites in which changes in DNA methylation are associated with genetic variation at proximal loci. We found that meQTLs are frequently associated with changes in methylation at multiple CpGs across regions of up to 3 kb. Interestingly, meQTLs are also frequently associated with variation in other properties of gene regulation, including histone modifications, DNase I accessibility, chromatin accessibility, and expression levels of nearby genes. These observations suggest that genetic variants may lead to coordinated molecular changes in all of these regulatory phenotypes. One plausible driver of coordinated changes in different regulatory mechanisms is variation in transcription factor (TF) binding. Indeed, we found that SNPs that change predicted TF binding affinities are significantly enriched for associations with DNA methylation at nearby CpGs.

Author Summary

DNA methylation is an important epigenetic mark that contributes to many biological processes including the regulation of gene expression. Genetic variation has been associated with quantitative changes in DNA methylation (meQTLs). We identified thousands of meQTLs using an assay that allowed us to measure methylation levels at around 300 thousand cytosines. We found that meQTLs are enriched with loci that is also associated with quantitative changes in gene expression, DNase I hypersensitivity, PolII occupancy, and a number of histone marks. This suggests that many molecular events are likely regulated in concert. Finally, we found that changes in transcription factor binding as well as transcription factor abundance are associated with changes in DNA methylation near transcription factor binding sites. This work contributes to our understanding of the regulation of DNA methylation in the larger context of gene regulatory landscape.
Год издания: 2008
Авторы: Peter Craig, Paul Dieppe, Sally MacIntyre, Susan Michie, Irwin Nazareth, Mark Petticrew
Источник: BMJ
Ключевые слова: Epigenetics and DNA Methylation, Genetic Associations and Epidemiology, Birth, Development, and Health
Другие ссылки: BMJ (PDF)
BMJ (HTML)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
Enlighten: Publications (The University of Glasgow) (HTML)
LSHTM Research Online (London School of Hygiene and Tropical Medicine) (HTML)
Open Research Exeter (University of Exeter) (PDF)
Open Research Exeter (University of Exeter) (HTML)
PubMed (HTML)