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Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease

Author

Listed:
  • Joshua Moss

    (The Hebrew University-Hadassah Medical School
    The Hebrew University of Jerusalem)

  • Judith Magenheim

    (The Hebrew University-Hadassah Medical School)

  • Daniel Neiman

    (The Hebrew University-Hadassah Medical School)

  • Hai Zemmour

    (The Hebrew University-Hadassah Medical School)

  • Netanel Loyfer

    (The Hebrew University of Jerusalem)

  • Amit Korach

    (Hadassah-Hebrew University Medical Center)

  • Yaacov Samet

    (Hadassah-Hebrew University Medical Center)

  • Myriam Maoz

    (Hadassah-Hebrew University Medical Center)

  • Henrik Druid

    (Karolinska Institutet
    The National Board of Forensic Medicine)

  • Peter Arner

    (Karolinska Institutet)

  • Keng-Yeh Fu

    (Karolinska Institutet)

  • Endre Kiss

    (Karolinska Institutet)

  • Kirsty L. Spalding

    (Karolinska Institutet
    Karolinska Institutet)

  • Giora Landesberg

    (Hadassah-Hebrew University Medical Center)

  • Aviad Zick

    (Hadassah-Hebrew University Medical Center)

  • Albert Grinshpun

    (Hadassah-Hebrew University Medical Center)

  • A. M. James Shapiro

    (University of Alberta)

  • Markus Grompe

    (Oregon Health & Science University)

  • Avigail Dreazan Wittenberg

    (The Hebrew University-Hadassah Medical School)

  • Benjamin Glaser

    (Hadassah-Hebrew University Medical Center)

  • Ruth Shemer

    (The Hebrew University-Hadassah Medical School)

  • Tommy Kaplan

    (The Hebrew University of Jerusalem)

  • Yuval Dor

    (The Hebrew University-Hadassah Medical School)

Abstract

Methylation patterns of circulating cell-free DNA (cfDNA) contain rich information about recent cell death events in the body. Here, we present an approach for unbiased determination of the tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types. The method is validated using in silico simulations as well as in vitro mixes of DNA from different tissue sources at known proportions. We show that plasma cfDNA of healthy donors originates from white blood cells (55%), erythrocyte progenitors (30%), vascular endothelial cells (10%) and hepatocytes (1%). Deconvolution of cfDNA from patients reveals tissue contributions that agree with clinical findings in sepsis, islet transplantation, cancer of the colon, lung, breast and prostate, and cancer of unknown primary. We propose a procedure which can be easily adapted to study the cellular contributors to cfDNA in many settings, opening a broad window into healthy and pathologic human tissue dynamics.

Suggested Citation

  • Joshua Moss & Judith Magenheim & Daniel Neiman & Hai Zemmour & Netanel Loyfer & Amit Korach & Yaacov Samet & Myriam Maoz & Henrik Druid & Peter Arner & Keng-Yeh Fu & Endre Kiss & Kirsty L. Spalding & , 2018. "Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07466-6
    DOI: 10.1038/s41467-018-07466-6
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    Citations

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    Cited by:

    1. Kobe Ridder & Huiwen Che & Kaat Leroy & Bernard Thienpont, 2024. "Benchmarking of methods for DNA methylome deconvolution," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Alicia-Marie Conway & Simon P. Pearce & Alexandra Clipson & Steven M. Hill & Francesca Chemi & Dan Slane-Tan & Saba Ferdous & A. S. Md Mukarram Hossain & Katarzyna Kamieniecka & Daniel J. White & Clai, 2024. "A cfDNA methylation-based tissue-of-origin classifier for cancers of unknown primary," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    3. Xiao Zhou & Zhen Cheng & Mingyu Dong & Qi Liu & Weiyang Yang & Min Liu & Junzhang Tian & Weibin Cheng, 2022. "Tumor fractions deciphered from circulating cell-free DNA methylation for cancer early diagnosis," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. 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.
    5. Peng Dai & Lucia Ruojia Wu & Sherry Xi Chen & Michael Xiangjiang Wang & Lauren Yuxuan Cheng & Jinny Xuemeng Zhang & Pengying Hao & Weijie Yao & Jabra Zarka & Ghayas C. Issa & Lawrence Kwong & David Yu, 2021. "Calibration-free NGS quantitation of mutations below 0.01% VAF," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    6. Grayson A. Herrgott & James M. Snyder & Ruicong She & Tathiane M. Malta & Thais S. Sabedot & Ian Y. Lee & Jacob Pawloski & Guilherme G. Podolsky-Gondim & Karam P. Asmaro & Jiaqi Zhang & Cara E. Cannel, 2023. "Detection of diagnostic and prognostic methylation-based signatures in liquid biopsy specimens from patients with meningiomas," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    7. 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.
    8. S. John Liu & Tim Casey-Clyde & Nam Woo Cho & Jason Swinderman & Melike Pekmezci & Mark C. Dougherty & Kyla Foster & William C. Chen & Javier E. Villanueva-Meyer & Danielle L. Swaney & Harish N. Vasud, 2024. "Epigenetic reprogramming shapes the cellular landscape of schwannoma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    9. Yaping Liu & Sarah C. Reed & Christopher Lo & Atish D. Choudhury & Heather A. Parsons & Daniel G. Stover & Gavin Ha & Gregory Gydush & Justin Rhoades & Denisse Rotem & Samuel Freeman & David W. Katz &, 2024. "FinaleMe: Predicting DNA methylation by the fragmentation patterns of plasma cell-free DNA," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    10. Lucia Ruojia Wu & Peng Dai & Michael Xiangjiang Wang & Sherry Xi Chen & Evan N. Cohen & Gitanjali Jayachandran & Jinny Xuemeng Zhang & Angela V. Serrano & Nina Guanyi Xie & Naoto T. Ueno & James M. Re, 2022. "Ensemble of nucleic acid absolute quantitation modules for copy number variation detection and RNA profiling," Nature Communications, Nature, vol. 13(1), pages 1-9, December.

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