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DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes1. Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells2-5. Here we describe a human methylome 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 more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.
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Understanding how the same DNA sequence is interpreted differently in different cell types is a fundamental challenge of biology. Gene expression, DNA accessibility and chromatin packaging are well-established essential determinants of cellular phenotype. Underneath these lies DNA methylation, a stable epigenetic mark that underpins the lifelong maintenance of cellular identity.
Available human DNA methylation datasets suffer from major limitations. Multiple studies that have characterized methylomes of embryonic development, differentiation, cancer or other settings6-9 have relied on the Illumina BeadChip platforms, which are limited to a predefined subset of 450,000 or 860,000 CpG methylation sites, representing just 3% of around 30 million CpG sites in the human genome10. In addition, by measuring each CpG site independently, such assays overlook coordinated patterns of DNA methylation occurring in blocks, the critical functional units of DNA methylation11,12.
Most DNA methylation analyses interrogated primarily bulk tissue, thus precluding the study of minority cell types such as tissue-resident immune cells, fibroblasts or endothelial cells, whereas others analysed cultured cells, which may contain nonphysiological...