Men are 3-4 times more likely to develop bladder cancer (BCa) than women are. In fact, the incidence of almost all types of cancer is consistently higher in males than in females. The key difference in genetic makeup between males and females is the sex chromosome complement (XX versus XY). We do not know, however, the extent to which sex chromosomes are responsible for the gender difference of BCa susceptibility. Neither do we know whether sex chromosomes enhance or reduce the gonadal hormone-dependent sexually dimorphic phenotypes. Epigenetic programming in the sexual dimorphism is an emerging field. At present, essentially nothing is known about the epigenetic mechanism of the gender difference in BCa susceptibility. Many epigenetic programs regulate histone methylation to maintain active or silent states of chromatin. The X- linked histone demethylase, Utx/Kdm6a, is an epigenetic regulator that functions in a sex-specific manner during development; this gene is mutated in over 25% of human BCa cases. Furthermore, mutation rates of epigenetic regulators are significantly higher in human BCa than all other epithelial cancers studied in The Cancer Genome Atlas (TCGA) projects. Thus, the X-linked, Utx-dependent epigenetic program may impart sex-specific gene expression differences in bladder urothelium, and consequently influence BCa susceptibility. To address questions highlighted above, we will first use a novel mouse model, which consist of the "four core genotypes"-XX and XY- females with ovaries, and XY-Sry and XXSry males with testes-to investigate whether the gender difference in BCa susceptibility depends on the sex chromosome complement and/or the gonadal types. Second, we will determine whether the Utx-dependent epigenetic program causes the sex disparity in BCa incidence using a mouse conditional knockout (cKO) strategy. Third, we will use genomic technology to identify sexually dimorphic genetic and epigenetic targets of the Utx-dependent epigenetic program. Identification of these molecular features may shed light onto the underlying epigenetic mechanism of the sex disparities of BCa. Together, the proposed studies will significantly improve our understanding of the gender difference in BCa susceptibility, and may substantially alter our view of the emerging paradigm of epigenetic programing in the sex disparities in cancer incidence, and could potentially lead to future epigenetic-based treatment strategies to BCa.