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Megakaryocyte- and erythroblast-specific cell-free DNA patterns in plasma and platelets reflect thrombopoiesis and erythropoiesis levels

Author

Listed:
  • Joshua Moss

    (the Hebrew University-Hadassah Medical School
    Hadassah-Hebrew University Medical Center)

  • Roni Ben-Ami

    (the Hebrew University-Hadassah Medical School)

  • Ela Shai

    (Hadassah-Hebrew University Medical Center)

  • Ofer Gal-Rosenberg

    (the Hebrew University-Hadassah Medical School)

  • Yosef Kalish

    (Hadassah-Hebrew University Medical Center)

  • Agnes Klochendler

    (the Hebrew University-Hadassah Medical School)

  • Gordon Cann

    (GRAIL, LLC.)

  • Benjamin Glaser

    (Hadassah University Medical Center and Faculty of Medicine, the Hebrew University)

  • Ariela Arad

    (Hadassah-Hebrew University Medical Center)

  • Ruth Shemer

    (the Hebrew University-Hadassah Medical School)

  • Yuval Dor

    (the Hebrew University-Hadassah Medical School)

Abstract

Circulating cell-free DNA (cfDNA) fragments are a biological analyte with extensive utility in diagnostic medicine. Understanding the source of cfDNA and mechanisms of release is crucial for designing and interpreting cfDNA-based liquid biopsy assays. Using cell type-specific methylation markers as well as genome-wide methylation analysis, we determine that megakaryocytes, the precursors of anuclear platelets, are major contributors to cfDNA (~26%), while erythroblasts contribute 1–4% of cfDNA in healthy individuals. Surprisingly, we discover that platelets contain genomic DNA fragments originating in megakaryocytes, contrary to the general understanding that platelets lack genomic DNA. Megakaryocyte-derived cfDNA is increased in pathologies involving increased platelet production (Essential Thrombocythemia, Idiopathic Thrombocytopenic Purpura) and decreased upon reduced platelet production due to chemotherapy-induced bone marrow suppression. Similarly, erythroblast cfDNA is reflective of erythrocyte production and is elevated in patients with thalassemia. Megakaryocyte- and erythroblast-specific DNA methylation patterns can thus serve as biomarkers for pathologies involving increased or decreased thrombopoiesis and erythropoiesis, which can aid in determining the etiology of aberrant levels of erythrocytes and platelets.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43310-2
    DOI: 10.1038/s41467-023-43310-2
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    References listed on IDEAS

    as
    1. Hai Zemmour & David Planer & Judith Magenheim & Joshua Moss & Daniel Neiman & Dan Gilon & Amit Korach & Benjamin Glaser & Ruth Shemer & Giora Landesberg & Yuval Dor, 2018. "Non-invasive detection of human cardiomyocyte death using methylation patterns of circulating DNA," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    2. 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 & H, 2023. "A DNA methylation atlas of normal human cell types," Nature, Nature, vol. 613(7943), pages 355-364, January.
    3. 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.
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