Global regulation of the histone mark H3K36me2 underlies epithelial plasticity and metastatic progression.

Epithelial plasticity - reversible modulation of a cell's epithelial and mesenchymal features - is associated with tumor metastasis and chemoresistance, leading causes of cancer mortality. While different master transcription factors and epigenetic modifiers have been implicated in this process in various contexts, the extent to which a unifying, generalized mechanism of transcriptional regulation underlies epithelial plasticity remains largely unknown. Here, through targeted CRISPR-Cas9 screening, we discovered two histone-modifying enzymes involved in the writing and erasing of H3K36me2 that act reciprocally to regulate epithelial-mesenchymal identity, tumor differentiation, and metastasis. Using a K-to-M histone mutant to directly inhibit H3K36me2, we found that global modulation of the mark is a conserved mechanism underlying the mesenchymal state in various contexts. Mechanistically, regulation of H3K36me2 reprograms enhancers associated with master regulators of epithelial-mesenchymal state. Our results thus outline a unifying epigenome-scale mechanism by which a specific histone modification regulates cellular plasticity and metastasis in cancer.

上皮可塑性——细胞上皮和间充质特征的可逆调节——与肿瘤转移和化疗耐药相关，这是癌症死亡的主要原因。虽然在不同情况下，不同的主转录因子和表观遗传修饰因子都参与了这一过程，但转录调控的统一、通用机制在上皮可塑性中所起作用的程度在很大程度上仍然未知。在此，通过靶向CRISPR - Cas9筛选，我们发现了两种参与H3K36me2写入和擦除的组蛋白修饰酶，它们相互作用以调节上皮 - 间充质特性、肿瘤分化和转移。利用一种K - to - M组蛋白突变体直接抑制H3K36me2，我们发现该标记的整体调节是在各种情况下间充质状态的一种保守机制。从机制上讲，H3K36me2的调节会重新编程与上皮 - 间充质状态的主调节因子相关的增强子。因此，我们的结果勾勒出一种统一的表观基因组规模的机制，通过这种机制，一种特定的组蛋白修饰调节癌症中的细胞可塑性和转移。