Genome-wide DNA Methylation Analysis Identifies Kidney Epigenetic Dysregulation in a Cystinosis Mouse Model

Nephropathic cystinosis is a rare genetic disorder caused by cystine accumulation in lysosomes, resulting in early renal dysfunction and progressive kidney disease. While altered metabolic pathways, oxidative stress, and inflammation have been implicated in disease pathogenesis, the precise mechanisms driving its progression are still not fully understood. Recent studies indicate that epigenetic modifications, particularly DNA methylation (DNAm), play a crucial role in the development of chronic kidney disease. Building on this, we hypothesize that epigenetic dysregulation may also contribute to the progression of cystinosis.Methods. We performed a genome-wide DNAm analysis on the kidneys of 6-month-old Ctns?/? mice, a model for cystinosis, comparing them to wild-type (WT) controls. Our analysis revealed extensive DNAm alterations in cystinotic kidneys, with a marked hypermethylation pattern. These methylation changes were primarily found in genes and pathways crucial for kidney function, particularly those related to the physiology of the proximal tubules. Importantly, these DNAm alterations correlated with changes in gene expression, as validated by qPCR analyses of key genes in WT and Ctns-/- kidneys. Furthermore, in vitro treatment with the demethylating agent decitabine in human proximal tubular epithelial cells led to the upregulation of critical transporter genes, suggesting a potential therapeutic approach. These findings underscore the role of epigenetic regulation in cystinosis progression and suggest that DNAm could serve as a promising target for novel therapeutic strategies. DNA was extracted and analysed from whole kidneys of 6-months-old wild type or cystinotic mice