Abel Fothi, Francesco Demetrio Lofaro, Robbe Derudder, Alessia Mazzilli, Federica Boraldi, Olivier Vanakker, Daniela Quaglino, Tamas Aranyi
Affiliation(s):
Hun-ren Research Center For Natural Sciences, Institute Of Molecular Life Sciences, Budapest, Hungary / Semmelweis University, Department Of Molecular Biology, Budapest, Hungary
Objectives and status: Pseudoxanthoma Elasticum (PXE) is a heritable disorder marked by progressive calcification of elastic fiber–rich tissues due to loss-of-function mutations in the ABCC6 gene. While ABCC6 is predominantly expressed in hepatocytes and not in fibroblasts, PXE fibroblasts exhibit disease-associated phenotypic changes. This suggests that secondary, cell-autonomous mechanisms—potentially involving epigenetic regulation—contribute to disease manifestation in non-hepatic tissues. Notably, PXE fibroblasts also display mitochondrial dysfunction, which may influence epigenetic regulation and, in turn, contribute to ectopic calcification. We have therefore decided to investigate the genome-wide DNA methylation of PXE patients.
Methodology: We conducted genome-wide DNA methylation profiling of primary dermal fibroblasts from PXE patients (n=5) and age- and sex-matched controls (n=4) using the Illumina EPIC Array v2 (~930,000 CpG sites, >99% of genes). Proteomic analysis and methylation validation studies are ongoing in the same cell populations.
Findings: Principal Component Analysis (PCA) showed clear segregation between PXE and control fibroblasts. We identified 29 differentially methylated CpG sites (DMS) (p < 10⁻⁵), over 65% of which exhibited >20% methylation change. Notably, many DMSs mapped to loci associated with transcriptional regulation, chromatin remodeling, or fibrotic processes.
Significance: PXE fibroblasts exhibit distinct DNA methylation profiles compared to controls, implicating epigenetic dysregulation in PXE pathogenesis. Despite the small cohort size, the robustness of the methylation differences highlights the potential of epigenetic profiling in uncovering disease-related pathways and potential therapeutic targets in PXE.