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 cells^2,3,4,5. 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.

DNA 甲基化是控制基因表达和染色质组织的基本表观遗传标记，从而为了解细胞身份和发育过程提供了一个窗口¹ 。当前的数据集通常仅包含一小部分甲基化位点，并且通常基于在培养物中经历巨大变化的细胞系或包含未指定的细胞混合物的组织^2,3,4,5 。在这里，我们描述了基于深度全基因组亚硫酸氢盐测序的人类甲基化组图谱，允许对从 205 个健康组织样本中分选的 39 种细胞类型的数千个独特标记进行片段水平分析。相同细胞类型的复制品具有超过 99.5% 的相同性，这证明了细胞识别程序对环境扰动的稳健性。图谱的无监督聚类概括了组织个体发育的关键要素，并识别了胚胎发育以来保留的甲基化模式。单个细胞类型中独特的非甲基化基因座通常位于转录增强子中，并包含组织特异性转录调节因子的 DNA 结合位点。独特的高甲基化位点很罕见，并且富含 CpG 岛、Polycomb 靶点和 CTCF 结合位点，这表明在塑造细胞类型特异性染色质环中具有新的作用。该图谱为研究基因调控和疾病相关遗传变异提供了重要资源，并提供了大量用于液体活检的潜在组织特异性生物标志物。