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Cited by 656Epigenetics and DNA MethylationGenomics and Chromatin DynamicsGenetic Syndromes and Imprinting

A DNA methylation atlas of normal human cell types

Open access
Loyfer, Netanel, Magenheim, Judith, Peretz, Ayelet, Cann, Gordon, Bredno, Joerg, Klochendler, Agnes, Fox-Fisher, Ilana, Shabi-Porat, Sapir +41 more·2023·Nature
DOI 10.1038/s41586-022-05580-6PMC PMC9811898

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Abstract

DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes 1 . 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 2–5 . 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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Authors
Loyfer, N., Magenheim, J., Peretz, A., Cann, G., Bredno, J., Klochendler, A., Fox-Fisher, I., Shabi-Porat, S., Hecht, M., Pelet, T., Moss, J., Drawshy, Z., Amini, H., Moradi, P., Nagaraju, S., Bauman, D., Shveiky, D., Porat, S., Dior, U., Rivkin, G., Or, O., Hirshoren, N., Carmon, E., Pikarsky, A., Khalaileh, A., Zamir, G., Grinbaum, R., Abu Gazala, M., Mizrahi, I., Shussman, N., Korach, A., Wald, O., Izhar, U., Erez, E., Yutkin, V., Samet, Y., Rotnemer Golinkin, D., Spalding, K. L., Druid, H., Arner, P., Shapiro, A. M. J., Grompe, M., Aravanis, A., Venn, O., Jamshidi, A., Shemer, R., Dor, Y., Glaser, B., & Kaplan, T.
Affiliations
  • Hebrew University of Jerusalem (IL)
  • Grail (United States) (US)
  • Shaare Zedek Medical Center (IL)
  • Karolinska Institutet (SE)
  • Swedish National Board of Forensic Medicine (SE)
  • Karolinska University Hospital (SE)
  • University of Alberta (CA)
  • Oregon Health & Science University (US)
Corresponding author
  • Dor, Yuval
  • Kaplan, Tommy
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2023-01-04
Volume
613
Issue
7943
Pages
355-364
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-022-05580-6
PMC
PMC9811898
OpenAlex
W4313544615
Cited by
656
References
15
Citations by year
2026: 169 · 2025: 202 · 2024: 179 · 2023: 96 · 2022: 10
FWCI
58.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Leona M. and Harry B. Helmsley Charitable Trust
  • Hadassah Medical Organization
  • Human Islet Research Network
  • Israel Science Foundation (1250/18)
  • Stichting Diabetes Onderzoek Nederland
  • Leibniz-Gemeinschaft
  • National Institute of Diabetes and Digestive and Kidney Diseases (UC4DK116274, UC4DK104216)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
Keywords
DNA methylation, cell type-specific methylation, human cell types, whole-genome bisulfite sequencing, enhancers, CTCF binding sites, chromatin looping, CpG islands, tissue-specific biomarkers, liquid biopsy, epigenetics
MeSH terms
Whole Genome Sequencing, CCCTC-Binding Factor, Epigenome, Cell Line, Cells, Chromatin, DNA, Enhancer Elements, Genetic, Humans, Organ Specificity, Sulfites, CpG Islands, DNA Methylation, Epigenesis, Genetic, Embryonic Development, Polycomb-Group Proteins

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