Epigenetic, genomic, and proteomic changes are hallmarks of cancer development as well as of the aging syndromes. With an emphasis on those processes’ mice models of Ruijs-Aalfs syndrome and bladder cancer were studied. Our research group has identified mutations in the SPRTN gene as a cause of progeroid disorder known as Ruijs-Aalfs syndrome (RAS), a rare disease characterized by premature aging and the development of early-onset hepatocellular carcinoma. To study RAS more deeply we generated Sprtn knock-in mice (Sprtnki/ki) harboring the mutation found in RAS patients. These mice display phenotypes reminiscent of RAS but also abnormal nuclei, less condensed chromatin, and shorter telomeres. Thus, we profiled the epigenome of Sprtnki/ki mice by analyzing their methylome as well as chromatin landscape using sequencing and different molecular approaches. Global hypomethylation was observed and different chromatin accessibility, with global upregulation of mRNA affecting changes in lipid metabolism. Molecular testing identified the interaction of SPRTN with key epigenetics players - DNMT1 and UHRF1 revealing mechanistic insight into observed methylome changes. These data support the notion that the epigenome deregulation may be an underlying mechanism of the severe phenotype observed in RAS patients as well as in mutant mice. Because epigenetics, in particular DNA methylation, has recently been recognized as one of the pillars of aging and carcinogenesis, gaining insight into Spartan's role in epigenetics is of primary importance. We additionally studied DNA methylation signatures and its impacts on gene expression in mouse models of urinary bladder cancer (BC) following N-butyl-N-(4-hydroxybutyl)-nitrosamine administration. Because aberrant DNA methylation accompanied by changes in gene expression is an important element of cancer pathogenesis, we profiled the methylome and transcriptome of BC using sequencing approaches. Hypo- and hypermethylation were present in non-invasive BC, across CpGs of the genes involved in muscle- and neuronal-related pathways, but were not reflected in the expression of the respective genes. However, invasive tumors displayed only hypermethylation changes with alterations in gene expression in these genes. Our findings suggest that BC progression could be revealed through methylation profiling at its pre-invasive stage, which could assist in better monitoring of BC patients.