New Results

Methylation QTLs are associated with coordinated changes in transcription factor binding, histone modifications, and gene expression levels.

Nicholas E Banovich, Xun Lan, Graham McVicker, Bryce Van de Geijn, Jacob F Degner, John D. Blischak, Jonathan K. Pritchard, Yoav Gilad

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%) 11,752 methylation QTLs (meQTLs)?i.e., loci in which genetic variation is associated with changes in DNA methylation. 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. Taken together, our observations are consistent with a model whereby changes in TF binding may frequently drive coordinated changes in DNA methylation, histone modification, and gene expression levels.