Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a heritable disease characterized by bilateral renal enlargement due to the growth of cysts throughout the kidneys. Inheritance of a disease-causing mutation is required to develop ADPKD, which results in end-stage kidney disease and is associated with a high morbidity. The pathology underlying cyst formation is not well understood. To address this, we have previously shown the global methylome is altered in ADPKD tissue, suggesting a role of DNA methylation in disease-state renal tissue. As cysts are believed to arise independently, we hypothesize that DNA methylation changes vary accordingly. Here we further investigate the role of DNA methylation within independent cysts to characterize key intra-individual changes. We demonstrate that fragments within CpG islands and gene bodies harbor the greatest amount of variation across the ADPKD kidney, while intergenic fragments are comparatively stable. A proportion of variably methylated genes were also differentially methylated in ADPKD tissue. Our data provide evidence that individual molecular mechanisms are operating in the development of each cyst.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the bilateral accumulation of fluid-filled cysts within the kidneys
The role of DNA methylation in ADPKD is an emerging field of study and following our recent identification of site-specific DNA methylation changes in cystic renal tissue, we sought to investigate if these changes are seen consistently between individual cysts in a single patient
We have identified that in addition to whole tissue differentially methylated fragments (DMFs) being present in most single cysts, there are regions of heterogeneity in the DNA methylation of cysts across a single individual ADPKD patient
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the bilateral accumulation of fluid-filled cysts within the kidneys. While ADPKD is the most common heritable renal disease in humans, affecting. Methylation Variation in ADPKD Cysts an estimated 1–5 in 10,000 patients (Solazzo et al, 2018), treatment options for this disease are limited as there is still little understanding about the underlying cause of cystogenesis (Tan et al, 2011; Reed-Gitomer, 2014). The presence of a disease-causing mutation is required to develop ADPKD, a causal relationship between these mutations and the process of cystogenesis is not yet clearly elucidated. In atypical presentations of ADPKD, disease-causing mutations have been reported in GANAB (Porath et al, 2016) and DNAJB11 (Cornec-Le Gall et al, 2018). It is generally accepted that each ADPKD cyst arises by means of focal proliferation (ReedGitomer, 2014), where a single cell will acquire altered growth characteristics, rapidly proliferate and form a distinct cyst
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