A DNA methylation atlas of normal human cell types
2Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hadassah Medical Center and Faculty of Medicine, The Hebrew University of Jerusalem, Israel
3Department of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, The Hebrew University of Jerusalem, Israel
DNA methylation is a fundamental epigenetic mark that governs chromatin organization, cell identity, and gene expression. Here we describe a human methylation atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell-type are >99.5% identical, demonstrating robustness of cell identity programs to genetic variation and environmental perturbation.
Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny, and identifies methylation patterns retained since gastrulation. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Conversely, cell type-specific hyper-methylated loci are rare and enriched for CpG islands, polycomb targets, and CTCF binding sites, suggesting a novel role in shaping cell type-specific chromatin looping.
The atlas provides an essential resource for understanding cell type-specific gene regulation, interpretation of disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies for the analysis of circulating cell-free DNA fragments.