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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Despite improved initial therapies, a subgroup of patients with aggressive non-Hodgkin (A-NHL) and Hodgkin lymphomas (HL) will relapse after first remission. The optimal follow-up strategy for the detection of relapse has not been clarified and periodic imaging is not recommended in most written guidelines. We identified 125 patients with HL and A-NHL diagnosed between January 1993 and September 2008 who relapsed at least 1 month after the end of initial therapy. We assessed whether relapse was detected based on clinical signs or periodic computed tomography (CT), [(18)F] fluorodeoxyglucose positron emission tomography (PET), or combined PET/CT and whether the mode of detection influenced the pattern and outcome of relapsed disease. Overall, most relapses (62%) were diagnosed clinically especially in A-NHL and in patients with extranodal involvement at diagnosis (p < 0.05); however, relapses of HL occurring after 2001 when PET/CT became available were more commonly detected by routine imaging (p < 0.05). Imaging-detected relapse was not associated with improved survival. While clinical exam remains the most common mode of detecting relapse, our results suggest a potential role for routine PET/CT surveillance in HL patients; however, survival does not appear to be affected by mode of detection.

DNA methylation is a fundamental epigenetic mark that governs chromatin organization, cell identity, and gene expression. 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 207 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. Uniquely hyper-methylated loci are rare and are 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 interpretation of disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.