ABSTRACT Histone modifiers are amongst the most highly mutated genes in all forms of cancer, with the histone demethylase UTX (KDM6A) being one of the most frequent. UTX is mutated in several epithelial cancers including cutaneous squamous cell carcinoma (cSCC), the second most common type of all human malignancies. UTX is found on the X chromosome and is a major enhancer regulator. It establishes the active enhancer landscape through its histone demethylase activity as well as its ability to complex with other activating histone modifiers. UTX is also known to escape X inactivation creating a dosage disparity between males and females that may account for some of the sex specific differences observed for both the risk and severity of certain types of cancer, including cSCC. In support of this, when constitutively knocked out in all tissues, UTX loss results in embryonic lethality in all females, while ~25% of males survive to adulthood. Interestingly, UTY, the Y-linked paralog of UTX, retains minimal demethylase function but potentially compensates for loss of UTX through other mechanisms. In addition to its involvement in sex specific differences, UTX is implicated as a tumor suppressor in several epithelial cancers. Recently, UTX has also been shown to sense cellular oxygen. Accumulating data suggests that UTX is critical for proper cellular homeostasis and plays fundamental roles in development and carcinogenesis. However, despite this evidence and the high incidence of UTX mutations in cSCC, there is virtually no understanding of how this enzyme functions during epidermal homeostasis and carcinogenesis. To investigate this, we have generated mice with epidermal specific deletions of Utx where only female Utx knockout mice display any obvious abnormalities. Specifically, homozygous knockout female mice present with reduced size as well as erythematous, scaly skin compared to littermate controls. H&E staining of the skin harvested from these mice reveals premalignant changes such as epidermal hyperplasia. When knocked down in primary human keratinocytes UTX loss leads to dramatic transcriptional changes. Hypoxic response genes and those involved oxidative phosphorylation are among the most differentially expressed. These data provoke the hypothesis that UTX is critical for the proper homeostatic gene expression, and when lost lead to altered metabolism and higher cancer risk. To test this hypothesis, I will carry out the following aims: In Aim1 I will determine how Utx loss affects epidermal homeostasis in vivo and investigate its role in hypoxia and metabolism in the epidermis. In Aim2 I will use UV- radiation to induce tumorigenesis in our Utx knockout mouse model to determine if Utx acts as a tumor suppressor in the epidermis. I will also assess how tumor risk and severity is affected by Utx loss between males and females to glean insights about sex specific differences driven by UTX copy gene dosage. Furthermore, given the inherent reversi...