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Circulating cell-free DNA methylation patterns indicate cellular sources of allograft injury after liver transplant

Author

Listed:
  • Megan E. McNamara

    (Georgetown University)

  • Sidharth S. Jain

    (Georgetown University)

  • Kesha Oza

    (Georgetown University Medical Center
    MedStar Georgetown University Hospital)

  • Vinona Muralidaran

    (Georgetown University Medical Center)

  • Amber J. Kiliti

    (Georgetown University)

  • A. Patrick McDeed

    (Georgetown University)

  • Digvijay Patil

    (Georgetown University Medical Center)

  • Yuki Cui

    (Georgetown University Medical Center)

  • Marcel O. Schmidt

    (Georgetown University)

  • Anna T. Riegel

    (Georgetown University)

  • Alexander Kroemer

    (Georgetown University Medical Center)

  • Anton Wellstein

    (Georgetown University)

Abstract

Post-transplant complications reduce allograft and recipient survival. Current approaches for detecting allograft injury non-invasively are limited and do not differentiate between cellular mechanisms. Here, we monitor cellular damages after liver transplants from cell-free DNA (cfDNA) fragments released from dying cells into the circulation. We analyzed 130 blood samples collected from 44 patients at different time points after transplant. Sequence-based methylation of cfDNA fragments were mapped to an atlas of cell-type-specific DNA methylation patterns derived from 476 methylomes of purified cells. For liver cell types, DNA methylation patterns and multi-omic data integration show distinct enrichment in open chromatin and functionally important regulatory regions. We find that multi-tissue cellular damages post-transplant recover in patients without allograft injury during the first post-operative week. However, sustained elevation of hepatocyte and biliary epithelial cfDNA within the first month indicates early-onset allograft injury. Further, cfDNA composition differentiates amongst causes of allograft injury indicating the potential for non-invasive monitoring and intervention.

Suggested Citation

  • Megan E. McNamara & Sidharth S. Jain & Kesha Oza & Vinona Muralidaran & Amber J. Kiliti & A. Patrick McDeed & Digvijay Patil & Yuki Cui & Marcel O. Schmidt & Anna T. Riegel & Alexander Kroemer & Anton, 2025. "Circulating cell-free DNA methylation patterns indicate cellular sources of allograft injury after liver transplant," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60507-9
    DOI: 10.1038/s41467-025-60507-9
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    References listed on IDEAS

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