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Human DNA methylomes at base resolution show widespread epigenomic differences

Author

Listed:
  • Ryan Lister

    (Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA)

  • Mattia Pelizzola

    (Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA)

  • Robert H. Dowen

    (Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA)

  • R. David Hawkins

    (Ludwig Institute for Cancer Research,)

  • Gary Hon

    (Ludwig Institute for Cancer Research,)

  • Julian Tonti-Filippini

    (ARC Centre of Excellence in Plant Energy Biology, The University of Western Australia, Crawley, Western Australia 6009, Australia)

  • Joseph R. Nery

    (Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA)

  • Leonard Lee

    (Ludwig Institute for Cancer Research,)

  • Zhen Ye

    (Ludwig Institute for Cancer Research,)

  • Que-Minh Ngo

    (Ludwig Institute for Cancer Research,)

  • Lee Edsall

    (Ludwig Institute for Cancer Research,)

  • Jessica Antosiewicz-Bourget

    (Morgridge Institute for Research, Madison, Wisconsin 53707, USA
    Genome Center of Wisconsin, Madison, Wisconsin 53706, USA)

  • Ron Stewart

    (Morgridge Institute for Research, Madison, Wisconsin 53707, USA
    Genome Center of Wisconsin, Madison, Wisconsin 53706, USA)

  • Victor Ruotti

    (Morgridge Institute for Research, Madison, Wisconsin 53707, USA
    Genome Center of Wisconsin, Madison, Wisconsin 53706, USA)

  • A. Harvey Millar

    (ARC Centre of Excellence in Plant Energy Biology, The University of Western Australia, Crawley, Western Australia 6009, Australia)

  • James A. Thomson

    (Morgridge Institute for Research, Madison, Wisconsin 53707, USA
    Genome Center of Wisconsin, Madison, Wisconsin 53706, USA
    Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin 53715, USA
    University of Wisconsin-Madison, Madison, Wisconsin 53706, USA)

  • Bing Ren

    (Ludwig Institute for Cancer Research,
    University of California San Diego, La Jolla, California 92093, USA)

  • Joseph R. Ecker

    (Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA)

Abstract

DNA cytosine methylation is a central epigenetic modification that has essential roles in cellular processes including genome regulation, development and disease. Here we present the first genome-wide, single-base-resolution maps of methylated cytosines in a mammalian genome, from both human embryonic stem cells and fetal fibroblasts, along with comparative analysis of messenger RNA and small RNA components of the transcriptome, several histone modifications, and sites of DNA–protein interaction for several key regulatory factors. Widespread differences were identified in the composition and patterning of cytosine methylation between the two genomes. Nearly one-quarter of all methylation identified in embryonic stem cells was in a non-CG context, suggesting that embryonic stem cells may use different methylation mechanisms to affect gene regulation. Methylation in non-CG contexts showed enrichment in gene bodies and depletion in protein binding sites and enhancers. Non-CG methylation disappeared upon induced differentiation of the embryonic stem cells, and was restored in induced pluripotent stem cells. We identified hundreds of differentially methylated regions proximal to genes involved in pluripotency and differentiation, and widespread reduced methylation levels in fibroblasts associated with lower transcriptional activity. These reference epigenomes provide a foundation for future studies exploring this key epigenetic modification in human disease and development.

Suggested Citation

  • Ryan Lister & Mattia Pelizzola & Robert H. Dowen & R. David Hawkins & Gary Hon & Julian Tonti-Filippini & Joseph R. Nery & Leonard Lee & Zhen Ye & Que-Minh Ngo & Lee Edsall & Jessica Antosiewicz-Bourg, 2009. "Human DNA methylomes at base resolution show widespread epigenomic differences," Nature, Nature, vol. 462(7271), pages 315-322, November.
    • Handle: RePEc:nat:nature:v:462:y:2009:i:7271:d:10.1038_nature08514
    DOI: 10.1038/nature08514
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    Citations

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    Cited by:

    1. Jamie L. Endicott & Paula A. Nolte & Hui Shen & Peter W. Laird, 2022. "Cell division drives DNA methylation loss in late-replicating domains in primary human cells," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Singer Meromit & Engström Alexander & Schönhuth Alexander & Pachter Lior, 2011. "Determining Coding CpG Islands by Identifying Regions Significant for Pattern Statistics on Markov Chains," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 10(1), pages 1-27, September.
    3. Brendan Evano & Diljeet Gill & Irene Hernando-Herraez & Glenda Comai & Thomas M Stubbs & Pierre-Henri Commere & Wolf Reik & Shahragim Tajbakhsh, 2020. "Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation," PLOS Genetics, Public Library of Science, vol. 16(10), pages 1-21, October.
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    5. Jiang Li & Fangxu Han & Tongqi Yuan & Wei Li & Yue Li & Harry X. Wu & Hairong Wei & Shihui Niu, 2023. "The methylation landscape of giga-genome and the epigenetic timer of age in Chinese pine," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
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    9. David Cheishvili & Chifat Wong & Mohammad Mahbubul Karim & Mohammad Golam Kibria & Nusrat Jahan & Pappu Chandra Das & Md. Abul Khair Yousuf & Md. Atikul Islam & Dulal Chandra Das & Sheikh Mohammad Noo, 2023. "A high-throughput test enables specific detection of hepatocellular carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
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    11. Christopher G Bell & Sarah Finer & Cecilia M Lindgren & Gareth A Wilson & Vardhman K Rakyan & Andrew E Teschendorff & Pelin Akan & Elia Stupka & Thomas A Down & Inga Prokopenko & Ian M Morison & Jonat, 2010. "Integrated Genetic and Epigenetic Analysis Identifies Haplotype-Specific Methylation in the FTO Type 2 Diabetes and Obesity Susceptibility Locus," PLOS ONE, Public Library of Science, vol. 5(11), pages 1-12, November.
    12. Allegra Angeloni & Skye Fissette & Deniz Kaya & Jillian M. Hammond & Hasindu Gamaarachchi & Ira W. Deveson & Robert J. Klose & Weiming Li & Xiaotian Zhang & Ozren Bogdanovic, 2024. "Extensive DNA methylome rearrangement during early lamprey embryogenesis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    13. Xuelong Yao & Zongyang Lu & Zhanying Feng & Lei Gao & Xin Zhou & Min Li & Suijuan Zhong & Qian Wu & Zhenbo Liu & Haofeng Zhang & Zeyuan Liu & Lizhi Yi & Tao Zhou & Xudong Zhao & Jun Zhang & Yong Wang , 2022. "Comparison of chromatin accessibility landscapes during early development of prefrontal cortex between rhesus macaque and human," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    14. Yongjun Piao & Wanxue Xu & Kwang Ho Park & Keun Ho Ryu & Rong Xiang, 2021. "Comprehensive Evaluation of Differential Methylation Analysis Methods for Bisulfite Sequencing Data," IJERPH, MDPI, vol. 18(15), pages 1-15, July.
    15. Guodong Wu & Nengjun Yi & Devin Absher & Degui Zhi, 2011. "Statistical Quantification of Methylation Levels by Next-Generation Sequencing," PLOS ONE, Public Library of Science, vol. 6(6), pages 1-12, June.
    16. Olbricht Gayla R. & Craig Bruce A. & Doerge Rebecca W., 2012. "Incorporating Genomic Annotation into a Hidden Markov Model for DNA Methylation Tiling Array Data," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 11(5), pages 1-37, November.
    17. Rakesh Chettier & Lesa Nelson & James W Ogilvie & Hans M Albertsen & Kenneth Ward, 2015. "Haplotypes at LBX1 Have Distinct Inheritance Patterns with Opposite Effects in Adolescent Idiopathic Scoliosis," PLOS ONE, Public Library of Science, vol. 10(2), pages 1-11, February.
    18. Jason A. Carter & Léonie Strömich & Matthew Peacey & Sarah R. Chapin & Lars Velten & Lars M. Steinmetz & Benedikt Brors & Sheena Pinto & Hannah V. Meyer, 2022. "Transcriptomic diversity in human medullary thymic epithelial cells," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    19. Lacey Michelle R. & Baribault Carl & Ehrlich Melanie, 2013. "Modeling, simulation and analysis of methylation profiles from reduced representation bisulfite sequencing experiments," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 12(6), pages 723-742, December.
    20. Ruth V. Nichols & Brendan L. O’Connell & Ryan M. Mulqueen & Jerushah Thomas & Ashley R. Woodfin & Sonia Acharya & Gail Mandel & Dmitry Pokholok & Frank J. Steemers & Andrew C. Adey, 2022. "High-throughput robust single-cell DNA methylation profiling with sciMETv2," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    21. Xue Yue & Zhiyuan Xie & Moran Li & Kai Wang & Xiaojing Li & Xiaoqing Zhang & Jian Yan & Yimeng Yin, 2022. "Simultaneous profiling of histone modifications and DNA methylation via nanopore sequencing," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    22. Yu Xiaoqing & Sun Shuying, 2016. "Comparing five statistical methods of differential methylation identification using bisulfite sequencing data," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 15(2), pages 173-191, April.
    23. Emanuele Raineri & Marc Dabad & Simon Heath, 2014. "A Note on Exact Differences between Beta Distributions in Genomic (Methylation) Studies," PLOS ONE, Public Library of Science, vol. 9(5), pages 1-5, May.
    24. Anyou Wang & Ying Du & Qianchuan He & Chunxiao Zhou, 2013. "A Quantitative System for Discriminating Induced Pluripotent Stem Cells, Embryonic Stem Cells and Somatic Cells," PLOS ONE, Public Library of Science, vol. 8(2), pages 1-10, February.
    25. Ihab Ansari & Llorenç Solé-Boldo & Meshi Ridnik & Julian Gutekunst & Oliver Gilliam & Maria Korshko & Timur Liwinski & Birgit Jickeli & Noa Weinberg-Corem & Michal Shoshkes-Carmel & Eli Pikarsky & Era, 2023. "TET2 and TET3 loss disrupts small intestine differentiation and homeostasis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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