DNA methylation modulates allograft survival and acute rejection after renal transplantation by regulating the mTOR pathway. Issue 2 (24th July 2020)

• Record Type: Journal Article
• Authors: Zhu, Chaohong; Xiang, Wenyu; Li, Bingjue; Wang, Yucheng; Feng, Shi; Wang, Cuili; Chen, Ying; Xie, Wenqing; Qu, Lihui; Huang, Hongfeng; Annunziata, Francesco; Nunna, Suneetha; Krepelova, Anna; Mohammad M. Rasa, Seyed; Neri, Francesco; Chen, Jianghua; Jiang, Hong
• Is Part Of: American journal of transplantation. Volume 21:Issue 2(2021)
• Page Start: 567
• Page End: 581
• Publication Date: 2020-07-24
• Subjects: basic (laboratory) research/science -- clinical research/practice -- genetics -- graft survival -- immunosuppressant – mechanistic target of rapamycin (mTOR) -- immunosuppression/immune modulation -- kidney (allograft) function/dysfunction -- kidney transplantation/nephrology -- microarray array -- rejection: acute; Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/ajt.16183
• Languages: English
• ISSNs: 1600-6135

Abstract

Abstract : Acute rejection (AR) can lead to allograft dysfunction following renal transplantation, despite immunosuppressive treatments. Accumulating evidence points out a role for epigenetic modification in immune responses. However, the mechanism and contribution of DNA methylation in allograft survival remain unclear. In this study, we followed up patients who successively experienced end‐stage renal disease, renal transplantation with allograft function or dysfunction, and hemodialysis. Peripheral blood mononuclear cells were collected at different time points for analysis of the DNA methylation. Epigenetic modifier analysis was also performed to explore its effect of methylation in a mouse model of AR. Compared with the allograft‐stable cohort, patients who experienced AR‐induced allograft dysfunction demonstrated more changes in methylation patterns. Pathway analysis revealed that the hypermethylated areas in the allograft dysfunction group were associated with genes related to the mechanistic target of rapamycin (mTOR) signaling pathway. Moreover, in the mouse AR model, treatment with the DNA methyltransferase inhibitor—decitabine regulated the Th1/2/17/regulatory T cell (Treg cell) immune response via its demethylating role in the suppressing the activity of the mTOR pathway, which ultimately ameliorated renal allograft‐related inflammatory injuries. These results revealed that changes in methylation accompany AR‐induced allograft dysfunction after renal transplantation. Epigenetics may provide new insights into predicting and improving allograft survival. Abstract : Whole‐genome bisulfite sequencing explores epigenetic changes in renal transplant recipients, revealing enhanced hypermethylation of genes enriched in immune‐related pathways.