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A DNA methylation atlas of normal human cell types

Author

Listed:
  • Netanel Loyfer

    (The Hebrew University of Jerusalem)

  • Judith Magenheim

    (Hebrew University of Jerusalem)

  • Ayelet Peretz

    (Hebrew University of Jerusalem)

  • Gordon Cann

    (GRAIL, Inc.)

  • Joerg Bredno

    (GRAIL, Inc.)

  • Agnes Klochendler

    (Hebrew University of Jerusalem)

  • Ilana Fox-Fisher

    (Hebrew University of Jerusalem)

  • Sapir Shabi-Porat

    (The Hebrew University of Jerusalem)

  • Merav Hecht

    (Hebrew University of Jerusalem)

  • Tsuria Pelet

    (Hebrew University of Jerusalem)

  • Joshua Moss

    (Hebrew University of Jerusalem
    Hadassah Hebrew University Medical Center)

  • Zeina Drawshy

    (Hebrew University of Jerusalem)

  • Hamed Amini

    (GRAIL, Inc.)

  • Patriss Moradi

    (GRAIL, Inc.)

  • Sudharani Nagaraju

    (GRAIL, Inc.)

  • Dvora Bauman

    (Hebrew University of Jerusalem)

  • David Shveiky

    (Hebrew University of Jerusalem)

  • Shay Porat

    (Hebrew University of Jerusalem)

  • Uri Dior

    (Hebrew University of Jerusalem)

  • Gurion Rivkin

    (Hebrew University of Jerusalem)

  • Omer Or

    (Hebrew University of Jerusalem)

  • Nir Hirshoren

    (Hebrew University of Jerusalem)

  • Einat Carmon

    (Hebrew University of Jerusalem
    Samson Assuta Ashdod University Hospital)

  • Alon Pikarsky

    (Hebrew University of Jerusalem)

  • Abed Khalaileh

    (Hebrew University of Jerusalem)

  • Gideon Zamir

    (Hebrew University of Jerusalem)

  • Ronit Grinbaum

    (Hebrew University of Jerusalem)

  • Machmud Abu Gazala

    (Hebrew University of Jerusalem)

  • Ido Mizrahi

    (Hebrew University of Jerusalem)

  • Noam Shussman

    (Hebrew University of Jerusalem)

  • Amit Korach

    (Hebrew University of Jerusalem)

  • Ori Wald

    (Hebrew University of Jerusalem)

  • Uzi Izhar

    (Hebrew University of Jerusalem)

  • Eldad Erez

    (Hebrew University of Jerusalem)

  • Vladimir Yutkin

    (Hebrew University of Jerusalem)

  • Yaacov Samet

    (Shaare Zedek Medical Center)

  • Devorah Rotnemer Golinkin

    (Hebrew University of Jerusalem)

  • Kirsty L. Spalding

    (Karolinska Institutet)

  • Henrik Druid

    (Karolinska Institutet
    The National Board of Forensic Medicine)

  • Peter Arner

    (Department of Medicine (H7) and Karolinska University Hospital, Karolinska Institutet)

  • A. M. James Shapiro

    (University of Alberta)

  • Markus Grompe

    (Papé Family Pediatric Research Institute, Oregon Health & Science University)

  • Alex Aravanis

    (GRAIL, Inc.
    Illumina, Inc.)

  • Oliver Venn

    (GRAIL, Inc.)

  • Arash Jamshidi

    (GRAIL, Inc.)

  • Ruth Shemer

    (Hebrew University of Jerusalem)

  • Yuval Dor

    (Hebrew University of Jerusalem)

  • Benjamin Glaser

    (Hebrew University of Jerusalem)

  • Tommy Kaplan

    (The Hebrew University of Jerusalem
    Hebrew University of Jerusalem)

Abstract

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.

Suggested Citation

  • Netanel Loyfer & Judith Magenheim & Ayelet Peretz & Gordon Cann & Joerg Bredno & Agnes Klochendler & Ilana Fox-Fisher & Sapir Shabi-Porat & Merav Hecht & Tsuria Pelet & Joshua Moss & Zeina Drawshy & H, 2023. "A DNA methylation atlas of normal human cell types," Nature, Nature, vol. 613(7943), pages 355-364, January.
  • Handle: RePEc:nat:nature:v:613:y:2023:i:7943:d:10.1038_s41586-022-05580-6
    DOI: 10.1038/s41586-022-05580-6
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    Citations

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    Cited by:

    1. André Bortolini Silveira & Alexandre Houy & Olivier Ganier & Begüm Özemek & Sandra Vanhuele & Anne Vincent-Salomon & Nathalie Cassoux & Pascale Mariani & Gaelle Pierron & Serge Leyvraz & Damian Rieke , 2024. "Base-excision repair pathway shapes 5-methylcytosine deamination signatures in pan-cancer genomes," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Joshua Moss & Roni Ben-Ami & Ela Shai & Ofer Gal-Rosenberg & Yosef Kalish & Agnes Klochendler & Gordon Cann & Benjamin Glaser & Ariela Arad & Ruth Shemer & Yuval Dor, 2023. "Megakaryocyte- and erythroblast-specific cell-free DNA patterns in plasma and platelets reflect thrombopoiesis and erythropoiesis levels," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    3. Tianyu Zhu & Huige Tong & Zhaozhen Du & Stephan Beck & Andrew E. Teschendorff, 2024. "An improved epigenetic counter to track mitotic age in normal and precancerous tissues," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. Jiaqi Liu & Lijun Dai & Qiang Wang & Chenghao Li & Zhichao Liu & Tongyang Gong & Hengyi Xu & Ziqi Jia & Wanyuan Sun & Xinyu Wang & Minyi Lu & Tongxuan Shang & Ning Zhao & Jiahui Cai & Zhigang Li & Hon, 2024. "Multimodal analysis of cfDNA methylomes for early detecting esophageal squamous cell carcinoma and precancerous lesions," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Kate E. Stanley & Tatjana Jatsenko & Stefania Tuveri & Dhanya Sudhakaran & Lore Lannoo & Kristel Calsteren & Marie Borre & Ilse Parijs & Leen Coillie & Kris Bogaert & Rodrigo Almeida Toledo & Liesbeth, 2024. "Cell type signatures in cell-free DNA fragmentation profiles reveal disease biology," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Michaël Noë & Dimitrios Mathios & Akshaya V. Annapragada & Shashikant Koul & Zacharia H. Foda & Jamie E. Medina & Stephen Cristiano & Christopher Cherry & Daniel C. Bruhm & Noushin Niknafs & Vilmos Ad, 2024. "DNA methylation and gene expression as determinants of genome-wide cell-free DNA fragmentation," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    7. Theodore Sakellaropoulos & Catherine Do & Guimei Jiang & Giulia Cova & Peter Meyn & Dacia Dimartino & Sitharam Ramaswami & Adriana Heguy & Aristotelis Tsirigos & Jane A. Skok, 2024. "MethNet: a robust approach to identify regulatory hubs and their distal targets from cancer data," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    8. Pui Pik Law & Liudmila A. Mikheeva & Francisco Rodriguez-Algarra & Fredrika Asenius & Maria Gregori & Robert A. E. Seaborne & Selin Yildizoglu & James R. C. Miller & Hemanth Tummala & Robin Mesnage & , 2024. "Ribosomal DNA copy number is associated with body mass in humans and other mammals," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    9. Xu Hua & Hui Zhou & Hui-Chen Wu & Julia Furnari & Corina P. Kotidis & Raul Rabadan & Jeanine M. Genkinger & Jeffrey N. Bruce & Peter Canoll & Regina M. Santella & Zhiguo Zhang, 2024. "Tumor detection by analysis of both symmetric- and hemi-methylation of plasma cell-free DNA," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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