A DNA methylation atlas of normal human cell types

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, Hamed Amini, Patriss Moradi, Sudharani Nagaraju, Dvora Bauman, David Shveiky, Shay Porat, Uri Dior, Gurion Rivkin, Omer Or, Nir Hirshoren, Einat Carmon, Alon Pikarsky, Abed Khalaileh, Gideon Zamir, Ronit Grinbaum, Machmud Abu Gazala, Ido Mizrahi, Noam Shussman, Amit Korach, Ori Wald, Uzi Izhar, Eldad Erez, Vladimir Yutkin, Yaacov Samet, Devorah Rotnemer Golinkin, Kirsty L. Spalding, Henrik Druid, Peter Arner, A. M. James Shapiro, Markus Grompe, Alex Aravanis, Oliver Venn, Arash Jamshidi, Ruth Shemer, Yuval Dor (), Benjamin Glaser () and Tommy Kaplan ()
Additional contact information
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
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
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
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.
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

Nature, 2023, vol. 613, issue 7943, 355-364

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-022-05580-6

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