Eun Kyung Ko, Amy Anderson, Carina D’souza, Jonathan Zou, Sijia Huang, Sohyun Cho, Faizan Alawi, Stephen Prouty, Vivian Lee, Sora Yoon, Keegan Krick, Yoko Horiuchi, Kai Ge, John T. Seykora, Brian C. Capell. Disruption of H3K36 methylation provokes cellular plasticity to drive aberrant glandular formation and squamous carcinogenesis. Developmental Cell. January 9, 2024. doi: https://doi.org/10.1016/j.devcel.2023.12.007.
Highlights
• Disruption of H3K36 methylation via H3K36M expression drives epithelial plasticity
• This triggers epithelial glandulogenesis while also increasing cancer susceptibility
• H3K36M rewires the global and genome-wide H3K36me2 and H3K27me3 epigenetic landscape
• These chromatin changes suppress differentiation genes while activating glandular genes
Summary
Chromatin organization is essential for maintaining cell-fate trajectories and developmental programs. Here, we find that disruption of H3K36 methylation dramatically impairs normal epithelial differentiation and development, which promotes increased cellular plasticity and enrichment of alternative cell fates. Specifically, we observe a striking increase in the aberrant generation of excessive epithelial glandular tissues, including hypertrophic salivary, sebaceous, and meibomian glands, as well as enhanced squamous tumorigenesis. These phenotypic and gene expression manifestations are associated with loss of H3K36me2 and rewiring of repressive H3K27me3, changes we also observe in human patients with glandular hyperplasia. Collectively, these results have identified a critical role for H3K36 methylation in both in vivo epithelial cell-fate decisions and the prevention of squamous carcinogenesis and suggest that H3K36 methylation modulation may offer new avenues for the treatment of numerous common disorders driven by altered glandular function, which collectively affect large segments of the human population.