A human DNA methylation atlas reveals principles of cell type-specific methylation and identifies thousands of cell type-specific regulatory elements

Netanel Loyfer ¹ Judith Magenheim ² Ayelet Peretz ² Gordon Cann ³ Joerg Bredno ³ Agnes Klochendler ² Ilana Fox-Fisher ² Sapir Shabi-Porat ¹ Merav Hecht ² Tsuria Pelet ² Joshua Moss ² Zeina Drawshy ² Hamed Amini ³ Patriss Moradi ³ Sudharani Nagaraju ³ Dvora Bauman ⁴ David Shveiky ⁴ Shay Porat ⁴ Gurion Rivkin ⁴ Omer Or ⁴ Nir Hirshoren ⁴ Einat Carmon ⁴ Alon Pikarsky ⁴ Abed Khalaileh ⁴ Gideon Zamir ⁴ Ronit Grinboim ⁴ Machmud Abu Gazala ⁴ Ido Mizrahi ⁴ Noam Shussman ⁴ Amit Korach ⁴ Ori Wald ⁴ Uzi Izhar ⁴ Eldad Erez ⁴ Vladimir Yutkin ⁴ Yaacov Samet ⁶ Devorah Rotnemer Golinkin ⁵ Kirsty L. Spalding ⁷ Henrik Druid ⁸ Peter Arner ⁹ A.M. James Shapiro ¹⁰ Markus Grompe ¹¹ Alex Aravanis ³ Oliver Venn ³ Arash Jamshidi ³ Ruth Shemer ² Yuval Dor ² Benjamin Glaser ⁵ Tommy Kaplan ^1,2

¹Computer Science, Hebrew University
²Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hadassah Medical Center and Faculty of Medicine, Hebrew University
³GRAIL, GRAIL Inc.
⁴Hadassah Medical Center and Faculty of Medicine, Hebrew University
⁵Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, Hebrew University
⁶Vascular Surgery, Shaare Zedek Medical Center
⁷Cell and Molecular Biology, Karolinska Institutet
⁸Oncology-Pathology, Karolinska Institutet
⁹Medicine, Karolinska Institutet
¹⁰Surgery, University of Alberta
¹¹Papé Family Pediatric Research Institute, Oregon Health & Science University

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 developmental elements, whereas 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 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.