Methylation QTLs are associated with coordinated changes in transcription factor binding, histone modifications, and gene expression levels [Bisulfite-Seq]. Homo sapiens

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. Overall design: Whole genomic DNA from 10 Yoruba HapMap individuals and spiked in unmethylated lambda phage DNA was bisuflite converted using the Invitrogen MethylCode Bisulfite Conversion Kit and sequenced using a Illumina HiSeq 2000

DNA甲基化是基因表达的重要表观遗传调控因子。过往研究已揭示遗传变异与甲基化水平之间存在广泛关联，但二者间的具体机制关联仍未阐明。为填补这一研究空白，我们采集了来自64名国际人类基因组单体型图（HapMap）约鲁巴个体的淋巴母细胞系（LCLs）中约30万个基因座的甲基化数据，并对其中10名个体获取了全基因组亚硫酸氢盐测序数据。我们以10%的错误发现率（False Discovery Rate，FDR）筛选得到13915个顺式甲基化数量性状位点（cis methylation QTLs，meQTLs），即DNA甲基化变化与邻近基因座遗传变异存在关联的CpG位点。研究发现，meQTLs常与长达3kb区域内多个CpG位点的甲基化变化相关联。值得注意的是，meQTLs还常与基因调控的其他多种特征变异相关，包括组蛋白修饰、DNase I敏感性、染色质可及性以及邻近基因的表达水平。上述结果表明，遗传变异可能引发上述所有调控表型的协同分子变化。不同调控机制产生协同变化的一个合理驱动因素是转录因子（Transcription Factor，TF）结合的变异。事实上，我们发现改变预测转录因子结合亲和力的单核苷酸多态性（Single Nucleotide Polymorphisms，SNPs），在与邻近CpG位点DNA甲基化相关的位点中显著富集。实验整体设计：我们从10名约鲁巴HapMap个体中提取全基因组DNA，并掺入未甲基化的λ噬菌体DNA，随后使用Invitrogen MethylCode Bisulfite Conversion Kit完成亚硫酸氢盐转化，再通过Illumina HiSeq 2000测序平台进行测序。