Genome-Wide DNA Methylation in Polycystic Kidney Disease

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a heritable renal disease that causes the enlargement of kidneys due to the bilateral development of fluid-filled cysts. This results in end-stage kidney disease in adults and a reduced life expectancy.

While it is known that a mutation within a PKD-causing gene is required for the development of ADPKD, the underlying mechanisms causing cystogenesis and allowing the progression of disease are not well understood.

As a result of this poor understanding there are few treatment options for patients with ADPKD, therefore a large proportion of patients will progress to end-stage renal disease for which they will need dialysis or renal transplantation.

Epigenetic modifications including DNA methylation are known to be altered in neoplasia, for which there are now several FDA-approved therapeutic drugs. As there are many similarities between ADPKD and neoplasia, we postulate that like tumour tissue, ADPKD tissue contains differentially methylated regions that may be exploited for future therapeutic discovery.

To investigate this, we have performed reduced representation bisulfite sequencing (RRBS) on four ADPKD kidney tissue samples, and three non-ADPKD kidney tissue samples. In this analysis we confirm that there are 13 regions in the genome with differential methylation, and there is a global trend of hypomethylation in ADPKD. Furthermore, the 3’ end of the PKD associated gene PKD1 shows increased methylation associated with increased mRNA expression. To investigate whether DNA methylation changes are universally changed in ADPKD cysts, we performed RRBS on a further eight ADPKD samples, each from unique cysts from a single ADPKD patient. In this analysis there were differential methylation patterns in each cyst, however these changes were not consistent between cysts.

These data show trends in global methylation in ADPKD not previously reported, and methylation changes within the genes NAGLU and GET4 concomitant with gene expression, which require further investigation to identify their role in ADPKD.