Epithelial plasticity, reversible modulation of a cell's epithelial and mesenchymal features, is associated with tumor metastasis and chemoresistance, leading causes of cancer mortality. Although 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-to-mesenchymal identity, tumor differentiation, and metastasis. Using a lysine-to-methionine 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-to-mesenchymal state. Our results thus outline a unifying epigenome-scale mechanism by which a specific histone modification regulates cellular plasticity and metastasis in cancer. Significance: Although epithelial plasticity contributes to cancer metastasis and chemoresistance, no strategies exist for pharmacologically inhibiting the process. Here, we show that global regulation of a specific histone mark, H3K36me2, is a universal epigenome-wide mechanism that underlies epithelial-to-mesenchymal transition and mesenchymal-to-epithelial transition in carcinoma cells. These results offer a new strategy for targeting epithelial plasticity in cancer. This article is highlighted in the In This Issue feature, [p. 747][1] [1]: /lookup/volpage/10/747?iss=6

中文翻译：

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组蛋白标记 H3K36me2 的全球调控是上皮可塑性和转移进展的基础。

上皮可塑性是细胞上皮和间充质特征的可逆调节，与肿瘤转移和化学抗性相关，是癌症死亡的主要原因。尽管不同的主转录因子和表观遗传修饰符在各种情况下都与这一过程有关，但转录调控的统一、普遍机制在多大程度上是上皮可塑性的基础仍然是未知的。在这里，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，它们相互调节上皮间质的同一性、肿瘤分化和转移。使用赖氨酸-蛋氨酸组蛋白突变体直接抑制 H3K36me2，我们发现标记的全局调制是在各种情况下间充质状态背后的保守机制。从机制上讲，H3K36me2 的调节会重新编程与上皮-间充质状态的主要调节因子相关的增强子。因此，我们的结果概述了一种统一的表观基因组尺度机制，通过该机制，特定的组蛋白修饰可调节癌症中的细胞可塑性和转移。意义：虽然上皮可塑性有助于癌症转移和化学抗性，但尚无药理学抑制该过程的策略。在这里，我们展示了特定组蛋白标记 H3K36me2 的全局调节是一种普遍的表观基因组范围机制，是癌细胞中上皮-间充质转化和间充质-上皮转化的基础。这些结果为靶向癌症上皮可塑性提供了一种新策略。本文在“本期”功能中突出显示，[p。747][1][1]：/lookup/volpage/10/747?iss=6