Circulating cell-free DNA methylation patterns indicate cellular sources of allograft injury after liver transplant
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.
Authors
- Vinona Muralidaran (ORCID: https://orcid.org/0000-0002-0544-495X)
- A. Patrick McDeed (ORCID: https://orcid.org/0000-0003-3380-4112)
- Alexander Kroemer (ORCID: https://orcid.org/0000-0002-9842-4973)
- Sidharth Jain (ORCID: https://orcid.org/0000-0002-6263-651X)
- Marcel O. Schmidt (ORCID: https://orcid.org/0000-0002-3991-2766)
- Yuki Cui (ORCID: https://orcid.org/0009-0005-8810-2435)
- Digvijay Patil
- Megan E. McNamara (ORCID: https://orcid.org/0000-0002-2591-0567)
- Anton Wellstein (ORCID: https://orcid.org/0000-0002-0570-4950)
- Anna T. Riegel (ORCID: https://orcid.org/0000-0001-6585-8612)
- Kesha Oza
- Amber J. Kiliti (ORCID: https://orcid.org/0000-0002-8581-6222)
Institutions
- Georgetown University (US)
- Georgetown University Medical Center (US)
- MedStar Georgetown University Hospital (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-06-17
- DOI
- https://doi.org/10.1038/s41467-025-60507-9
- Citations
- 4
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Japan Agency for Medical Research and Development
- Genome British Columbia
- European Commission
- Chinese University of Hong Kong
- National Institutes of Health
- Canadian Institutes of Health Research
- Japan Science and Technology Agency
- Korea National Institute of Health
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- Core Research for Evolutional Science and Technology
- National Bioscience Database Center