SETD2是一种H3K36三甲基转移酶，在肺腺癌中是最常见的表观遗传修饰因子之一，其突变频率约为9%。然而，SETD2功能缺失如何促进肿瘤发生仍不清楚。使用条件性Setd2-KO小鼠，我们证明Setd2缺陷加速了KrasG12D驱动的肺部肿瘤起始，增加了肿瘤负担，并显著降低了小鼠的生存率。集成染色质可及性和转录组分析揭示了一个可能的SETD2肿瘤抑制模型，即SETD2缺失激活嵌入内部的增强子驱动癌基因转录输出，包括KRAS转录特征和PRC2被抑制的目标，通过调节染色质可及性和组蛋白伴侣招募。重要的是，SETD2缺失使KRAS突变型肺癌对组蛋白伴侣（FACT）复合物或转录延伸的抑制在体内外敏感。总的来说，我们的研究不仅揭示了SETD2失去的如何塑造表观基因组学和转录景观以促进肿瘤发生的机制，而且还确定了SETD2突变癌症的潜在治疗策略。

SETD2, a H3K36 trimethyltransferase, is the most frequently mutated epigenetic modifier in lung adenocarcinoma, with a mutation frequency of approximately 9%. However, how SETD2 loss of function promotes tumorigenesis remains unclear. Using conditional Setd2-KO mice, we demonstrated that Setd2 deficiency accelerated the initiation of KrasG12D-driven lung tumorigenesis, increased tumor burden, and significantly reduced mouse survival. An integrated chromatin accessibility and transcriptome analysis revealed a potentially novel tumor suppressor model of SETD2 in which SETD2 loss activates intronic enhancers to drive oncogenic transcriptional output, including the KRAS transcriptional signature and PRC2-repressed targets, through regulation of chromatin accessibility and histone chaperone recruitment. Importantly, SETD2 loss sensitized KRAS-mutant lung cancer to inhibition of histone chaperones, the FACT complex, or transcriptional elongation both in vitro and in vivo. Overall, our studies not only provide insight into how SETD2 loss shapes the epigenetic and transcriptional landscape to promote tumorigenesis, but they also identify potential therapeutic strategies for SETD2 mutant cancers.