GSE69894
Mapping of variable DNA methylation across multiple cell types defines a dynamic regulatory landscape of the human genome
DNA methylation is an important epigenetic modification involved in many biological processes and diseases. Many studies have mapped DNA methylation changes associated with embryogenesis, cell differentiation and cancer at a genome-wide scale. Our understanding of genome-wide DNA methylation changes in a developmental or disease-related context has been steadily growing. However, the investigation of which CpGs are variably methylated in different normal cell or tissue types is still limited. Here we present an in-depth analysis of 54 single-CpG-resolution DNA methylomes of normal human cell types by integrating high-throughput sequencing-based methylation data. We find that the percentage of unmethylated CpGs is relatively fixed regardless of cell type. However, which CpGs are unmethylated is cell-type specific. We categorize the 26 million human autosomal CpGs based on their methylation levels across multiple cell types to identify variably methylated CpGs. Among all the autosomal CpGs, 22.6% exhibit variable DNA methylation across cell types included in our study. These variably methylated CpGs form 66 thousand variably methylated regions (VMRs), encompassing 11% of the genome. By integrating a multitude of genomic data, we found that VMRs enrich for histone modifications indicative of enhancers, suggesting their role as regulatory elements marking cell type specificity. VMRs enrich for transcription factor binding sites in a tissue-dependent manner. Importantly, they enrich for GWAS variants, suggesting VMRs could potentially be implicated in disease and complex traits. Taken together, our results highlight the link among CpG methylation variation, genetic variation and disease risk in a tissue-specific manner for many human cell types. Overall design: Processed data includes new Samples and 75 Samples from  GSE16368 and 2 Samples from  GSE51565.