MYC enhancer invasion promotes prognostic cancer type-specific gene programs through an epigenetic switch [CAGE-seq]. MYC enhancer invasion promotes prognostic cancer type-specific gene programs through an epigenetic switch [CAGE-seq]

The transcription factor MYC is overexpressed in most cancers, where it drives multiple hallmarks of cancer progression. MYC is known to promote oncogenic transcription by binding to active promoters. In addition, MYC has also been shown to invade distal enhancers when expressed at oncogenic levels, but this enhancer binding has been proposed to have low gene-regulatory potential. Here, we demonstrate that MYC enhancer binding directly promotes cancer type-specific gene programs predictive of poor patient prognosis. MYC induces transcription of enhancer RNA through recruitment of RNAPII, rather than regulating RNAPII pause-release as is the case at promoters. This is mediated by MYC-induced H3K9 demethylation by KDM3A and acetylation by GCN5, leading to enhancer-specific BRD4 recruitment through its bromodomains, which facilitates RNAPII recruitment. Thus, we propose that MYC drives prognostic cancer type-specific gene programs by promoting RNAPII recruitment to enhancers through induction of an epigenetic switch. Overall design: CAGE-seq during MYC inhibition using KJ-PYR-9 in BT549 triple negative breast cancer cells

转录因子MYC（transcription factor MYC）在绝大多数癌症中呈过表达状态，可驱动癌症进展的多项核心特征。已有研究证实，MYC可通过结合活性启动子促进致癌转录。此外，当MYC以致癌水平表达时，还可侵袭远端增强子区域，但此前学界认为此类增强子结合事件的基因调控潜能较为有限。本研究证实，MYC的增强子结合可直接介导与患者不良预后相关的癌症类型特异性基因程序。MYC并非如启动子区域那般调控RNA聚合酶II（RNA polymerase II，RNAPII）的暂停释放，而是通过招募RNA聚合酶II来诱导增强子RNA的转录。该调控过程由MYC诱导的KDM3A介导的H3K9去甲基化与GCN5介导的组蛋白乙酰化所驱动，进而通过其溴结构域（bromodomains）招募BRD4至增强子特异性位点，最终促进RNA聚合酶II的招募。据此，我们提出：MYC可通过诱导表观遗传开关，促进RNA聚合酶II向增强子的招募，进而驱动与预后相关的癌症类型特异性基因程序。整体实验设计：在BT549三阴性乳腺癌细胞中使用KJ-PYR-9抑制MYC表达后开展CAGE-seq检测。