Background: We hypothesize that following early graft damage (e.g., ischemia reperfusion injury) post-kidney transplantation (KT), the graft response to injury and repair involve changes in DNA methylation (DNAm) and might influence long-term graft outcomes. Hereby, we assessed the dynamics of DNAm across 1) pre-implantation biopsies (PI) 2) post-reperfusion biopsies (PR) and 3) >24 months post kidney transplantation (KT).

Methods: Infinium 450K methylation (n = 96) and gene expression (n = 182) arrays were performed in PI, PR and KT renal allograft biopsies and analyzed. Integrative analyses of differentially methylated (Dme) CpGs and corresponding differential gene expression were performed at each matched time points. Genome runner was used to assess distribution and enrichment of Dme CpG sites along regulatory features. Principal component analysis showed how the different samples classified based on their Dme patterns.

Results: PI allografts showed Dme CpGs when classified based on progression to allograft dysfunction versus normal function. 1,188 CpG sites were Dme affecting genes involved in inflammation and metabolism. When paired PI and PR allografts were compared there was apparent change in DNAm of genes in pathways like NRF2 mediated oxidative stress response and functions like cellular assembly and organization, cell death and survival. Integration analysis showed Dme and expression of genes involved in energy metabolism, transporters and transcription factors important in regulation of immune response. Further, comparison of post-KT allografts with differential outcomes revealed 21,351 Dme CpG sites. The Dme CpGs observed at early time points were mostly hypomethylated and promoter associated. However, a shift in the pattern was observed in later stages. Equal number and hyper- and hypo-methylated CpGs were present and were interestingly located in gene bodies and in evolutionarily conserved tissue specific regions. Integration analysis corroborated with findings as gene expression changes in kidney tissue specific regions like tubular epithelium was observed.

Conclusions: Shift in DNAm patterns over time in renal allograft was evident with corresponding changes in gene expression patterns. Further understanding of these sequential changes might result in timely therapeutic interventions of the dynamic and reversible epigenetic modifications to avoid progression of graft injury.

CITATION INFORMATION: Bontha V, Maluf D, Dozmorov M, Bagchi D, Archer K, Mas V. DNA Methylation Dynamics from Ischemia/Reperfusion Injury to Long-Term Allograft Function. Am J Transplant. 2017;17 (suppl 3).

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