The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains.
The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains.
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DOI：
10.1101/gad.267583.115
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发表时间：
2015-07-15
影响因子：
10.5
通讯作者：
French CA
中科院分区：
文献类型：
--
作者：
Alekseyenko AA;Walsh EM;Wang X;Grayson AR;Hsi PT;Kharchenko PV;Kuroda MI;French CA
坚果中线癌(NMC)是鳞状细胞癌的一种亚型，由一种易位癌蛋白BRD4-NUT的产生驱动。Alekseyenko等人。研究发现，∼-NUT在患者肿瘤中形成了独特的核焦点，与BRD4NUT相关的BRD4NUT与BRD4NUT相关，BRD4NUT与BRD4NUT中前所未有的、高乙酰化的大小达2Mb的染色质相关。这些“巨核”似乎推动了NMC患者细胞和诱导表达BRD4-NUT的幼稚细胞中潜在DNA的转录。坚果中线癌(NMC)是鳞状细胞癌的一种亚型，是已知的人类最具侵袭性的实体恶性肿瘤之一。NMC是由一种易位癌蛋白BRD4-NUT的产生驱动的，该蛋白阻止NMC细胞的分化并推动其生长。∼-NUT在患者肿瘤中形成独特的核病灶，我们发现这与BRD4-NUT中前所未有的、高乙酰化的大小达2Mb的染色质相关。这些“巨核”似乎是乙酰化和乙酰化组蛋白结合的异常前馈循环的结果，乙酰化组蛋白驱动NMC患者细胞和诱导表达BRD4-NUT的幼稚细胞中潜在DNA的转录。Megadomain的位置通常是细胞谱系特有的；然而，cMYC和TP63区域在所有测试的NMC中都是靶点，并在肿瘤生长中发挥功能作用。Megadomain似乎起源于选定的预先存在的增强子，这些增强子逐渐加宽，但最终被拓扑相关结构域(TAD)边界所界定。因此，我们的发现为理解大规模染色质组织在正常和异常谱系特异性基因转录中所起的强大作用奠定了基础。
NUT midline carcinoma (NMC), a subtype of squamous cell cancer, is driven by the creation of a translocation oncoprotein, BRD4-NUT. Alekseyenko et al. found that BRD4-NUT forms distinctive nuclear foci in patient tumors, which correlate with ∼100 unprecedented, hyperacetylated expanses of chromatin that reach up to 2 Mb in size. These “megadomains” appear to drive transcription of underlying DNA in NMC patient cells and naïve cells induced to express BRD4-NUT. NUT midline carcinoma (NMC), a subtype of squamous cell cancer, is one of the most aggressive human solid malignancies known. NMC is driven by the creation of a translocation oncoprotein, BRD4-NUT, which blocks differentiation and drives growth of NMC cells. BRD4-NUT forms distinctive nuclear foci in patient tumors, which we found correlate with ∼100 unprecedented, hyperacetylated expanses of chromatin that reach up to 2 Mb in size. These “megadomains” appear to be the result of aberrant, feed-forward loops of acetylation and binding of acetylated histones that drive transcription of underlying DNA in NMC patient cells and naïve cells induced to express BRD4-NUT. Megadomain locations are typically cell lineage-specific; however, the cMYC and TP63 regions are targeted in all NMCs tested and play functional roles in tumor growth. Megadomains appear to originate from select pre-existing enhancers that progressively broaden but are ultimately delimited by topologically associating domain (TAD) boundaries. Therefore, our findings establish a basis for understanding the powerful role played by large-scale chromatin organization in normal and aberrant lineage-specific gene transcription.