Mutant p53 shapes the enhancer landscape of cancer cells in response to chronic immune signaling.
Mutant p53 shapes the enhancer landscape of cancer cells in response to chronic immune signaling.
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DOI：
10.1038/s41467-017-01117-y
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发表时间：
2017-09-29
影响因子：
16.6
通讯作者：
Lauberth SM
中科院分区：
文献类型：
--
作者：
Rahnamoun H;Lu H;Duttke SH;Benner C;Glass CK;Lauberth SM
炎症影响癌症的发生、发展和癌症治疗的疗效，但免疫信号传导驱动癌细胞转录组改变的机制仍不清楚。使用ChIP-seq、RNA-seq和GRO-seq，我们在此证明了肿瘤促进性p53突变体与主促炎调节因子NFκB的结合存在全局重叠，NFκB驱动增强子和基因激活的改变以响应慢性TNF-α信号传导。我们发现p53突变体直接与NFκB相互作用，并且这两种因子在不同的活性增强子组中影响另一种因子的结合。反过来，需要这些因子的同时和合作结合来调节RNAPII募集、增强子RNA的合成和肿瘤促进基因的激活。总的来说，这些发现建立了一种机制，通过这种机制，慢性TNF-α信号传导协调突变型p53和NFκB之间的功能相互作用，从而改变促癌基因表达模式。已知炎症会影响癌症的发展，但免疫信号驱动转化的机制仍不清楚。在这里，作者提供了证据表明，慢性TNF-α信号促进增强子结合和突变型p53和NFκB之间的转录相互作用。
Inflammation influences cancer development, progression, and the efficacy of cancer treatments, yet the mechanisms by which immune signaling drives alterations in the cancer cell transcriptome remain unclear. Using ChIP-seq, RNA-seq, and GRO-seq, here we demonstrate a global overlap in the binding of tumor-promoting p53 mutants and the master proinflammatory regulator NFκB that drives alterations in enhancer and gene activation in response to chronic TNF-α signaling. We show that p53 mutants interact directly with NFκB and that both factors impact the other’s binding at diverse sets of active enhancers. In turn, the simultaneous and cooperative binding of these factors is required to regulate RNAPII recruitment, the synthesis of enhancer RNAs, and the activation of tumor-promoting genes. Collectively, these findings establish a mechanism by which chronic TNF-α signaling orchestrates a functional interplay between mutant p53 and NFκB that underlies altered patterns of cancer-promoting gene expression. Inflammation is known to affect cancer development, yet the mechanisms by which immune signaling drives transformation remain unclear. Here, the authors provide evidence that chronic TNF-α signaling promotes the enhancer binding and transcriptional interplay between mutant p53 and NFκB.
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影响因子：
56.9
作者：
CHO, YJ;GORINA, S;PAVLETICH, NP
通讯作者：
PAVLETICH, NP
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
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
DOI：
10.1038/nrm3949
发表时间：
2015-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Heinz S;Romanoski CE;Benner C;Glass CK
通讯作者：
Glass CK
影响因子：
64.5
作者：
Mullen AC;Orlando DA;Newman JJ;Lovén J;Kumar RM;Bilodeau S;Reddy J;Guenther MG;DeKoter RP;Young RA
通讯作者：
Young RA