SETD2 regulates chromatin accessibility and transcription to suppress lung tumorigenesis.
SETD2 regulates chromatin accessibility and transcription to suppress lung tumorigenesis.
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SETD 2调节染色质可及性和转录以抑制肺肿瘤发生。
DOI：
10.1172/jci.insight.154120
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发表时间：
2023-02-22
期刊：
影响因子：
8
通讯作者：
Cheng, Emily H.
中科院分区：
文献类型：
--
作者：
Xie, Yuchen;Sahin, Merve;Wakamatsu, Toru;Inoue-Yamauchi, Akane;Zhao, Wanming;Han, Song;Nargund, Amrita M.;Yang, Shaoyuan;Lyu, Yang;Hsieh, James J.;Leslie, Christina S.;Cheng, Emily H.
SETD2是一种H3K36三甲基转移酶，是肺腺癌中最常发生突变的表观遗传修饰子，突变频率约为9%。然而，SETD2功能丧失如何促进肿瘤发生仍不清楚。使用条件Setd2- ko小鼠，我们证明Setd2缺乏加速了krasg12d驱动的肺肿瘤发生的启动，增加了肿瘤负荷，并显著降低了小鼠的存活率。一项整合染色质可及性和转录组分析揭示了一种潜在的新型SETD2肿瘤抑制模型，其中SETD2缺失激活内含子增强子，通过调节染色质可及性和组蛋白伴侣蛋白募集来驱动致癌转录输出，包括KRAS转录特征和prc2抑制靶标。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敏感，无论是在体外还是体内。总的来说，我们的研究不仅提供了SETD2缺失如何塑造表观遗传和转录景观以促进肿瘤发生的见解，而且还确定了SETD2突变型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.
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影响因子：
64.5
作者：
Kim J;Woo AJ;Chu J;Snow JW;Fujiwara Y;Kim CG;Cantor AB;Orkin SH
通讯作者：
Orkin SH
DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
7.7
作者：
Carvalho S;Vítor AC;Sridhara SC;Martins FB;Raposo AC;Desterro JM;Ferreira J;de Almeida SF
通讯作者：
de Almeida SF
影响因子：
16
作者：
Calo, Eliezer;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing