Cited by 690Epigenetics and DNA MethylationGenomics and Chromatin DynamicsGenetic Syndromes and Imprinting

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Human body epigenome maps reveal noncanonical DNA methylation variation

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Schultz, Matthew D., He, Yupeng, Whitaker, John W., Hariharan, Manoj, Mukamel, Eran A., Leung, Danny, Rajagopal, Nisha, Nery, Joseph R., Urich, Mark A., Chen, Huaming, Lin, Shin, Lin, Yiing, Jung, Inkyung, Schmitt, Anthony D., Selvaraj, Siddarth, Ren, Bing, Sejnowski, Terrence J., Wang, Wei, Ecker, Joseph R.·2015·Nature

DOI 10.1038/nature14465PMC PMC4499021

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Abstract

As part of the Epigenome Roadmap Project, genome-wide maps of DNA methylation and transcriptomes together with genomic DNA sequencing of 18 different primary human tissue types from 4 individuals are presented; analysis reveals widespread differential methylation of CG sites between tissues, and the presence of non-CG methylation in adult tissues. As part of the Epigenome Roadmap project, Joseph Ecker and colleagues provide genome-wide maps of DNA methylation and transcriptomes, in conjunction with genomic DNA sequencing, of 18 different primary human tissue types from four individuals. Analysis of the datasets reveals widespread differential methylation of CG sites between tissues, and methylation at regulatory elements generally has a negative correlation with gene expression as expected. A surprising amount of non-CG methylation is found in a subpopulation of cells in many tissues. Understanding the diversity of human tissues is fundamental to disease and requires linking genetic information, which is identical in most of an individual’s cells, with epigenetic mechanisms that could have tissue-specific roles. Surveys of DNA methylation in human tissues have established a complex landscape including both tissue-specific and invariant methylation patterns1,2. Here we report high coverage methylomes that catalogue cytosine methylation in all contexts for the major human organ systems, integrated with matched transcriptomes and genomic sequence. By combining these diverse data types with each individuals’ phased genome3, we identified widespread tissue-specific differential CG methylation (mCG), partially methylated domains, allele-specific methylation and transcription, and the unexpected presence of non-CG methylation (mCH) in almost all human tissues. mCH correlated with tissue-specific functions, and using this mark, we made novel predictions of genes that escape X-chromosome inactivation in specific tissues. Overall, DNA methylation in several genomic contexts varies substantially among human tissues.

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Maier, G., Hariharan, M., Ramasamy, R. K., Glina, A., van Rosmalen, L., Pathak, S. J., Deota, S., Patel, S., Lin, T., Lam, M. T. Y., et al. (2026) · Cell · doi:10.1016/j.cell.2026.09.044
Self-citation
Epigenetics in development, disease, and therapy: from mechanisms to clinical interventions
Ren, Y., Yang, L., Fei, B., Guo, R., Huang, J., Xu, Z., Wang, R., Zhang, P., Cao, D., Chen, P., et al. (2026) · Science China Life Sciences · doi:10.1007/s11427-025-3356-1
Epigenomic heterogeneity and spatial organization during human reprogrammingPreprint
Li, T. W., Langerman, J., Liu, C., Sun, Y., Baig, M. S., Kim, G., Fu, J., Ghoor, R. I., Zhang, Y., Behren, Z. V., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.10.15.757424
Softaware from Systematic identification and annotation of human methylation marks based on bisulfite sequencing methylomes reveals distinct roles of cell type-specific hypomethylation in the regulation of cell identity genes.
Liu, H., Liu, X., Zhang, S., Lv, J., Li, S., Shang, S., Jia, S., Wei, Y., Wang, F., Su, J., et al. (2016) · doi:10.24347/omic_19748_2.2.1/lm8664

Authors: Schultz, M. D., He, Y., Whitaker, J. W., Hariharan, M., Mukamel, E. A., Leung, D., Rajagopal, N., Nery, J. R., Urich, M. A., Chen, H., Lin, S., Lin, Y., Jung, I., Schmitt, A. D., Selvaraj, S., Ren, B., Sejnowski, T. J., Wang, W., & Ecker, J. R.
Affiliations: Salk Institute for Biological Studies (US)
University of California San Diego (US)
Ludwig Cancer Research (US)
Stanford University (US)
Washington University in St. Louis (US)
Corresponding author: Ecker, Joseph R.
ORCID: He, Yupeng
Whitaker, John W.
Hariharan, Manoj
Mukamel, Eran A.
Leung, Danny
Nery, Joseph R.
Chen, Huaming
Lin, Shin
Lin, Yiing
Jung, Inkyung
Schmitt, Anthony D.
Ren, Bing
Wang, Wei
Ecker, Joseph R.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2015-06-01
Volume: 523
Issue: 7559
Pages: 212-216
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature14465
PMC: PMC4499021
OpenAlex: W1506411903
Cited by: 690
References: 30
Citations by year: 2026: 30 · 2025: 43 · 2024: 39 · 2023: 61 · 2022: 61 · 2021: 65 · 2020: 80 · 2019: 69 · 2018: 81 · 2017: 63 · 2016: 68 · 2015: 28
FWCI: 34.75
Type: journal article
Language: en
Update notices: erratum (2015-11-25)
Open access: hybrid
doi.org
Licence: cc-by-nc-sa
creativecommons.org/licenses/by-nc-sa/3.0/ (tdm)
creativecommons.org/licenses/by-nc-sa/3.0/ (vor)
Locations: Nature (publishedVersion, cc-by-nc-sa)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
RePEc: Research Papers in Economics (submittedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: Howard Hughes Medical Institute
Gordon and Betty Moore Foundation
Mary K. Chapman Foundation
University of Texas at Austin
National Institutes of Health
National Heart, Lung, and Blood Institute (R00HL119617, K99HL119617, F32HL110473)
National Institute of General Medical Sciences (T32GM008666)
National Institute of Neurological Disorders and Stroke (R00NS080911, K99NS080911)
National Institute of Environmental Health Sciences (U01ES017166, R01ES024984)
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, non-CG methylation, tissue-specific methylation, partially methylated domains, allele-specific methylation, X chromosome inactivation escape, gene expression, regulatory elements
MeSH terms: Age Factors, Alleles, Chromosome Mapping, Female, Gene Expression Regulation, Humans, Male, Organ Specificity, Genetic Variation, DNA Methylation, Gene Expression Profiling, Epigenesis, Genetic

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Human body epigenome maps reveal noncanonical DNA methylation variation

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