Epigenetic regulation in transplant rejection and tolerance: mechanisms and therapeutic prospects

Epigenetics modulates gene expression and plays a pivotal role in numerous immune disorders. Over the past two decades, increasing evidence has indicated that epigenetic regulation contributes to transplant rejection and immune tolerance. Four primary epigenetic mechanisms-DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs (ncRNAs)-exert distinct effects on rejection after transplantation. Therefore, understanding the epigenetic mechanisms of rejection provides novel avenues for inducing immune tolerance and developing strategies to prolong graft survival and patient longevity. This review outlines the history of epigenetics and highlights landmark events since the term was coined. Furthermore, we summarize epigenetic research methodologies and describe the four primary general mechanisms of epigenetic regulation. We subsequently focus on recent studies supporting the role of epigenetic regulation in distinct pathological processes of solid organ transplantation (namely, ischemia‒reperfusion injury, acute rejection, and chronic rejection) and graft-vs.-host disease following hematopoietic stem cell transplantation. Finally, we discuss the clinical applications of epigenetics in transplant rejection, including predictive diagnostics and the induction of immune tolerance, to guide the future development of improved rejection suppression therapies.