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H3K36M provokes cellular plasticity to drive aberrant glandular formation and squamous carcinogenesis

Epigenetic dysregulation is pervasive in cancer, frequently impairing normal tissue development and differentiation1. Beyond alterations in histone modifying enzymes, “oncohistone” mutations have been described across a variety of cancers2-4, although the in vivo effects and underlying mechanisms behind these observations have not been well- studied and remain unclear. Here, by inducing the in vivo expression of histone H3.3 carrying a lysine to methionine (K to M) mutation at position 36 (H3K36M) in self- renewing stratifying epithelial tissues, we show that the H3K36M oncohistone dramatically disrupts normal epithelial differentiation, leading to extensive tissue dysplasia characterized by a significant increase in mitotic, proliferative basal stem cells. Furthermore, this differentiation blockade promotes increased cellular plasticity and enrichment of alternate cell fates, and in particular the aberrant generation of excessive glandular tissue including both hypertrophic salivary, sebaceous, and meibomian glands. Upon carcinogen stress, H3K36M mice display markedly enhanced squamous tumorigenesis. These aberrant phenotypic and gene expression manifestations are associated with global loss of H3K36me2 and concomitant gain of H3K27me3. Collectively, these results have revealed a previously unknown critical role for H3K36 methylation in both the in vivo maintenance of proper epithelial cell fate decisions and the prevention of squamous carcinogenesis. Additionally, they suggest that H3K36 methylation modulation may offer new avenues for the regulation of numerous common disorders driven by over- or under-active glandular function.