TIGP (BIO)—DNA Methylation Informs Solid Organ Transplantation Outcomes

Abstract

Epigenetic regulation through DNA methylation has emerged as a powerful biomarker platform for understanding immune dysregulation and predicting clinical outcomes after solid organ transplantation. Across lung and kidney transplant cohorts, we applied targeted bisulfite sequencing (TBS-seq) to peripheral blood mononuclear cells and bronchoalveolar lavage samples to characterize methylation signatures associated with infection, cytomegalovirus (CMV) immunity, immunosuppression exposure, and chronic allograft dysfunction. In CMV-seropositive transplant recipients, latent CMV infection induced widespread remodeling of the immune methylome, including hyper-methylation of Polycomb-associated and neural development loci and hypo-methylation of immune activation pathways, enabling development of a CMV episcore predictive of post-transplant viremia risk. In kidney transplant recipients, anti-thymocyte globulin (ATG) induction therapy profoundly altered DNA methylation patterns associated with CD4⁺ T cell depletion and immune suppression, while methylation-based machine learning models predicted post-transplant infection risk more accurately than transcriptomic profiles. In lung transplant recipients, respiratory DNA methylation profiles obtained during the first year after transplantation predicted chronic lung allograft dysfunction (CLAD) with high accuracy and identified profibrotic methylation signatures involving lipid membrane and cytoskeletal pathways. Collectively, these studies demonstrate that DNA methylation captures durable immune and tissue remodeling after transplantation and supports the development of epigenetic biomarkers for individualized risk stratification, infection surveillance, and long-term graft outcome prediction.

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