Sarah A Bowden1, Euan J Rodger1,2, Michael Bates1, Aniruddha Chatterjee1,2, Michael R Eccles1,2, Cherie Stayner3. 1. Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. 2. Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand. 3. Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand, cherie.stayner@otago.ac.nz.
Abstract
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of fluid-filled cysts in the kidney and end stage renal disease by the fourth or fifth decade of life. Mutations in the PKD1 gene account for 85% of all cases of ADPKD. No curative therapy exists for patients affected by this disease and an underexplored avenue for the treatment of ADPKD is the targeting of epigenetic changes that occur during cystogenesis. Limited data exists on alterations in DNA methylation that are associated with ADPKD. Given the similarities between cyst growth and neoplasia, and the fact that 2 DNA methylation inhibitors are already Food and Drug Administration-approved for the treatment of myelodysplastic syndrome, we hypothesized that global DNA methylation patterns in ADPKD would parallel that observed in neoplasia, and which may provide an opportunity to treat ADPKD with epigenetic inhibitors. To address this hypothesis, we undertook a global DNA methylation analysis of human ADPKD kidney. METHODS: We generated single nucleotide resolution methylomes of cortical kidney tissue from individuals with ADPKD, and from non-ADPKD kidney tissue, using reduced representation bisulfite sequencing. Using quantitative reverse transcription polymerase chain reaction, we investigated expression of the PKD1 gene in both ADPKD and non-ADPKD kidney. RESULTS: We have shown that ADPKD-derived genomic DNA exhibits global hypomethylation when compared with non-ADPKD kidney, a pattern commonly observed in DNA methylation studies of tumor-derived tissue. We have also identified 13 discrete regions that are significantly differentially methylated in ADPKD compared to non-ADPKD, and 8 of these are gene specific. The PKD1 gene shows an increase in methylation at the 3' end of the gene body, but in contrast to previously published data, this is not associated with a decrease in PKD1 mRNA expression. CONCLUSION: This genome-scale single nucleotide resolution analysis of DNA methylation in human polycystic kidneys suggests that DNA methylation differences at specific loci are associated with ADPKD. Further exploration into the significance of these preliminary results may shed light on the disease process, and potentially reveal new therapeutic possibilities.
BACKGROUND:Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of fluid-filled cysts in the kidney and end stage renal disease by the fourth or fifth decade of life. Mutations in the PKD1 gene account for 85% of all cases of ADPKD. No curative therapy exists for patients affected by this disease and an underexplored avenue for the treatment of ADPKD is the targeting of epigenetic changes that occur during cystogenesis. Limited data exists on alterations in DNA methylation that are associated with ADPKD. Given the similarities between cyst growth and neoplasia, and the fact that 2 DNA methylation inhibitors are already Food and Drug Administration-approved for the treatment of myelodysplastic syndrome, we hypothesized that global DNA methylation patterns in ADPKD would parallel that observed in neoplasia, and which may provide an opportunity to treat ADPKD with epigenetic inhibitors. To address this hypothesis, we undertook a global DNA methylation analysis of human ADPKD kidney. METHODS: We generated single nucleotide resolution methylomes of cortical kidney tissue from individuals with ADPKD, and from non-ADPKD kidney tissue, using reduced representation bisulfite sequencing. Using quantitative reverse transcription polymerase chain reaction, we investigated expression of the PKD1 gene in both ADPKD and non-ADPKD kidney. RESULTS: We have shown that ADPKD-derived genomic DNA exhibits global hypomethylation when compared with non-ADPKD kidney, a pattern commonly observed in DNA methylation studies of tumor-derived tissue. We have also identified 13 discrete regions that are significantly differentially methylated in ADPKD compared to non-ADPKD, and 8 of these are gene specific. The PKD1 gene shows an increase in methylation at the 3' end of the gene body, but in contrast to previously published data, this is not associated with a decrease in PKD1 mRNA expression. CONCLUSION: This genome-scale single nucleotide resolution analysis of DNA methylation in humanpolycystic kidneys suggests that DNA methylation differences at specific loci are associated with ADPKD. Further exploration into the significance of these preliminary results may shed light on the disease process, and potentially reveal new therapeutic possibilities.
Authors: Sarah A Bowden; Peter A Stockwell; Euan J Rodger; Matthew F Parry; Michael R Eccles; Cherie Stayner; Aniruddha Chatterjee Journal: Front Genet Date: 2020-04-15 Impact factor: 4.599
Authors: Sarah A Bowden; Euan J Rodger; Aniruddha Chatterjee; Michael R Eccles; Cherie Stayner Journal: Int J Mol Sci Date: 2021-12-11 Impact factor: 5.923