Circulating, cell-free methylated DNA indicates cellular sources of allograft injury after liver transplant

McNamara, M. E.; Jain, S. S.; Oza, K.; Muralidaran, V.; Kiliti, A. J.; McDeed, A. P.; Patil, D.; Cui, Y.; Schmidt, M. O.; Riegel, A. T.; Kroemer, A. H. K.; Wellstein, A.

doi:10.1101/2024.04.04.588176

bioRxiv · 10.1101/2024.04.04.588176

Circulating, cell-free methylated DNA indicates cellular sources of allograft injury after liver transplant

McNamara, M. E.·Jain, S. S.·Oza, K.·Muralidaran, V.·Kiliti, A. J.·McDeed, A. P.·Patil, D.·Cui, Y.·Schmidt, M. O.·Riegel, A. T.·Kroemer, A. H. K.·Wellstein, A.

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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 patterns established to identify cell types in different organs. For liver cell types DNA methylation patterns and multi-omic data integration show distinct enrichment in open chromatin and regulatory regions functionally important for the respective cell types. 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 beyond the first week indicates early-onset allograft injury. Further, cfDNA composition differentiates amongst causes of allograft injury indicating the potential for non-invasive monitoring and timely intervention.

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McNamara, M. E., Jain, S. S., Oza, K., Muralidaran, V., Kiliti, A. J., McDeed, A. P., Patil, D., Cui, Y., Schmidt, M. O., Riegel, A. T., Kroemer, A. H. K., Wellstein, A.. 2024-04-05. Circulating, cell-free methylated DNA indicates cellular sources of allograft injury after liver transplant. https://doi.org/10.1101/2024.04.04.588176

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