Circulating cell-free DNA methylation patterns indicate cellular sources of allograft injury after liver transplant
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) frag...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-06-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60507-9 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850111816770781184 |
|---|---|
| author | 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 Wellstein |
| author_facet | 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 Wellstein |
| author_sort | Megan E. McNamara |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-00c748c3a5fa4df1924e7c7654798d4a |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-00c748c3a5fa4df1924e7c7654798d4a2025-08-20T02:37:33ZengNature PortfolioNature Communications2041-17232025-06-0116111710.1038/s41467-025-60507-9Circulating cell-free DNA methylation patterns indicate cellular sources of allograft injury after liver transplantMegan E. McNamara0Sidharth S. Jain1Kesha Oza2Vinona Muralidaran3Amber J. Kiliti4A. Patrick McDeed5Digvijay Patil6Yuki Cui7Marcel O. Schmidt8Anna T. Riegel9Alexander Kroemer10Anton Wellstein11Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown UniversityDepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown UniversityMedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and Center for Translational Transplant Medicine, Georgetown University Medical CenterMedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and Center for Translational Transplant Medicine, Georgetown University Medical CenterDepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown UniversityDepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown UniversityMedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and Center for Translational Transplant Medicine, Georgetown University Medical CenterMedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and Center for Translational Transplant Medicine, Georgetown University Medical CenterDepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown UniversityDepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown UniversityMedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and Center for Translational Transplant Medicine, Georgetown University Medical CenterDepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown UniversityAbstract 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.https://doi.org/10.1038/s41467-025-60507-9 |
| spellingShingle | 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 Wellstein Circulating cell-free DNA methylation patterns indicate cellular sources of allograft injury after liver transplant Nature Communications |
| title | Circulating cell-free DNA methylation patterns indicate cellular sources of allograft injury after liver transplant |
| title_full | Circulating cell-free DNA methylation patterns indicate cellular sources of allograft injury after liver transplant |
| title_fullStr | Circulating cell-free DNA methylation patterns indicate cellular sources of allograft injury after liver transplant |
| title_full_unstemmed | Circulating cell-free DNA methylation patterns indicate cellular sources of allograft injury after liver transplant |
| title_short | Circulating cell-free DNA methylation patterns indicate cellular sources of allograft injury after liver transplant |
| title_sort | circulating cell free dna methylation patterns indicate cellular sources of allograft injury after liver transplant |
| url | https://doi.org/10.1038/s41467-025-60507-9 |
| work_keys_str_mv | AT meganemcnamara circulatingcellfreednamethylationpatternsindicatecellularsourcesofallograftinjuryafterlivertransplant AT sidharthsjain circulatingcellfreednamethylationpatternsindicatecellularsourcesofallograftinjuryafterlivertransplant AT keshaoza circulatingcellfreednamethylationpatternsindicatecellularsourcesofallograftinjuryafterlivertransplant AT vinonamuralidaran circulatingcellfreednamethylationpatternsindicatecellularsourcesofallograftinjuryafterlivertransplant AT amberjkiliti circulatingcellfreednamethylationpatternsindicatecellularsourcesofallograftinjuryafterlivertransplant AT apatrickmcdeed circulatingcellfreednamethylationpatternsindicatecellularsourcesofallograftinjuryafterlivertransplant AT digvijaypatil circulatingcellfreednamethylationpatternsindicatecellularsourcesofallograftinjuryafterlivertransplant AT yukicui circulatingcellfreednamethylationpatternsindicatecellularsourcesofallograftinjuryafterlivertransplant AT marceloschmidt circulatingcellfreednamethylationpatternsindicatecellularsourcesofallograftinjuryafterlivertransplant AT annatriegel circulatingcellfreednamethylationpatternsindicatecellularsourcesofallograftinjuryafterlivertransplant AT alexanderkroemer circulatingcellfreednamethylationpatternsindicatecellularsourcesofallograftinjuryafterlivertransplant AT antonwellstein circulatingcellfreednamethylationpatternsindicatecellularsourcesofallograftinjuryafterlivertransplant |