Effects of DNA Methylation on Progression to Interstitial Fibrosis and Tubular Atrophy in Renal Allograft Biopsies

A Multi-Omics Approach

S. V. Bontha, Daniel Maluf, K. J. Archer, C. I. Dumur, M. G. Dozmorov, A. L. King, E. Akalin, T. F. Mueller, L. Gallon, Valeria Mas

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Progressive fibrosis of the interstitium is the dominant final pathway in renal destruction in native and transplanted kidneys. Over time, the continuum of molecular events following immunological and nonimmunological insults lead to interstitial fibrosis and tubular atrophy and culminate in kidney failure. We hypothesize that these insults trigger changes in DNA methylation (DNAm) patterns, which in turn could exacerbate injury and slow down the regeneration processes, leading to fibrosis development and graft dysfunction. Herein, we analyzed biopsy samples from kidney allografts collected 24 months posttransplantation and used an integrative multi-omics approach to understand the underlying molecular mechanisms. The role of DNAm and microRNAs on the graft gene expression was evaluated. Enrichment analyses of differentially methylated CpG sites were performed using GenomeRunner. CpGs were strongly enriched in regions that were variably methylated among tissues, implying high tissue specificity in their regulatory impact. Corresponding to this methylation pattern, gene expression data were related to immune response (activated state) and nephrogenesis (inhibited state). Preimplantation biopsies showed similar DNAm patterns to normal allograft biopsies at 2 years posttransplantation. Our findings demonstrate for the first time a relationship among epigenetic modifications and development of interstitial fibrosis, graft function, and inter-individual variation on long-term outcomes.

Original languageEnglish (US)
Pages (from-to)3060-3075
Number of pages16
JournalAmerican Journal of Transplantation
Volume17
Issue number12
DOIs
StatePublished - Dec 1 2017

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DNA Methylation
Atrophy
Allografts
Fibrosis
Kidney
Biopsy
Transplants
Gene Expression
Organ Specificity
MicroRNAs
Epigenomics
Methylation
Renal Insufficiency
Regeneration
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

Cite this

Effects of DNA Methylation on Progression to Interstitial Fibrosis and Tubular Atrophy in Renal Allograft Biopsies : A Multi-Omics Approach. / Bontha, S. V.; Maluf, Daniel; Archer, K. J.; Dumur, C. I.; Dozmorov, M. G.; King, A. L.; Akalin, E.; Mueller, T. F.; Gallon, L.; Mas, Valeria.

In: American Journal of Transplantation, Vol. 17, No. 12, 01.12.2017, p. 3060-3075.

Research output: Contribution to journalArticle

Bontha, S. V. ; Maluf, Daniel ; Archer, K. J. ; Dumur, C. I. ; Dozmorov, M. G. ; King, A. L. ; Akalin, E. ; Mueller, T. F. ; Gallon, L. ; Mas, Valeria. / Effects of DNA Methylation on Progression to Interstitial Fibrosis and Tubular Atrophy in Renal Allograft Biopsies : A Multi-Omics Approach. In: American Journal of Transplantation. 2017 ; Vol. 17, No. 12. pp. 3060-3075.
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