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.

染色质组织对于维持细胞命运轨迹和发育程序至关重要。在这里，我们发现 H3K36 甲基化的破坏会极大地损害正常的上皮分化和发育，从而促进细胞可塑性的增加和替代细胞命运的丰富。具体来说，我们观察到过度上皮腺组织的异常生成显着增加，包括肥大的唾液腺、皮脂腺和睑板腺，以及鳞状肿瘤发生的增强。这些表型和基因表达表现与 H3K36me2 的缺失和抑制性 H3K27me3 的重新连接有关，我们也在腺体增生患者中观察到这些变化。总的来说，这些结果确定了 H3K36 甲基化在体内上皮细胞命运决定和预防鳞状细胞癌发生中的关键作用，并表明 H3K36 甲基化调节可能为治疗由腺体功能改变引起的许多常见疾病提供新途径。这些共同影响着大部分人口。