Investigating the potential of epigenetic therapeutics to modify epithelial glands

Summary: Abstract Body: H3K36 methylation is crucial for maintaining cell fidelity, genomic stability, and proper transcription. To study the role of H3K36 methylation in both cancer and epithelial biology, we generated H3K36 mutant mice (H3K36M), which expressed H3K36M specifically in keratin 14-positive epithelial cells. We previously have shown that H3K36M mice display a significant reduction in body size and an outwardly aged phenotype along with striking hyperplastic glandular formation in the skin (sebaceous), eyelids (meibomian), and tongue (salivary gland) (Ko, et al. Dev Cell. 2024). More recently, we find that mice lacking Setd2 (Krt14-Cre; Setd2fl/fl, i.e. “Setd2 KO”), which is the sole methyltransferase for H3K36me3, also exhibit similar phenotypes to H3K36M mice, including sebaceous and meibomian gland abnormalities, albeit more mild. These phenotypes from both H3K36M and Setd2 KO mice are associated with a global loss of H3K36 methylation along with a concomitant genome-wide redistribution of repressive H3K27me3. Together, these results provoke the hypothesis that modulating the epigenome may serve as an effective method to modify epithelial glandular size and/or activity and treat disorders driven by either overactive or underactive glandular activity or development. In this presentation, we will present our results of our in vitro and in vivo therapeutic studies testing pharmacological modifiers of both H3K36 and H3K27 methylation, as well as new spatial transcriptomic data detailing the underlying mechanisms. Eun Kyung Ko¹, Brian Capell¹, John T. Seykora¹, Vivian Lee¹, Olingou Cyria¹, Ge Kai² 1. Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States. 2. National Institutes of Health, Bethesda, MD, United States. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics