HPV integration hijacks and multimerizes a cellular enhancer to generate a viral-cellular super-enhancer that drives high viral oncogene expression.
HPV integration hijacks and multimerizes a cellular enhancer to generate a viral-cellular super-enhancer that drives high viral oncogene expression.
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DOI：
10.1371/journal.pgen.1007179
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发表时间：
2018-01
期刊：
影响因子：
4.5
通讯作者：
McBride AA
中科院分区：
文献类型：
--
作者：
Warburton A;Redmond CJ;Dooley KE;Fu H;Gillison ML;Akagi K;Symer DE;Aladjem MI;McBride AA
人乳头瘤病毒（HPV）基因组整合到细胞染色质中在HPV相关癌症中很常见。整合是随机的，每个位点都是独特的，这取决于病毒如何整合以及在哪里整合。我们最近发现，串联整合的HPV 16可能导致形成一个超级增强子样元件，驱动病毒癌基因的转录。在这里，我们的特点，这个整合位点的染色质景观和基因组结构，以阐明机制，促进从头超级增强子的形成。使用下一代测序和分子梳理/纤维FISH，我们发现约26个拷贝的HPV 16整合到染色体2p23.2的基因间区域，散布着25 kb扩增的侧翼细胞DNA。这种散布的、共扩增的病毒-宿主模式在HPV相关癌症中很常见，在这里我们将其称为III型整合。编码病毒E6/E7癌基因的丰富的病毒-细胞融合转录物从整合基因座表达，并且包含病毒增强子和相邻扩增的细胞序列中的区域的染色质强烈富集超级增强子标记H3 K27 ac和Brd 4。值得注意的是，扩增的细胞序列中的峰对应于上皮细胞型特异性增强子。因此，HPV 16整合产生了一个超级增强子样元件，由串联散布的病毒上游调控区和细胞增强子组成，以驱动高水平的癌基因表达。致癌性人乳头瘤病毒（HPV）感染是约5%人类癌症的原因。许多这些癌症发展中的关键事件是病毒基因组整合到宿主染色质中。整合导致病毒癌基因的表达失调，这促进不受调节的细胞分裂和细胞突变的积累，最终导致癌症。在HPV阳性肿瘤中，整合位点侧翼的细胞序列的遗传重排和/或扩增是常见的，并且这可以影响来自整合位点的病毒癌基因的转录。我们展示了一个例子，其中HPV 16基因组整合到细胞组织特异性增强子附近，随后病毒DNA和侧翼细胞序列被共扩增到串联散布的病毒细胞序列阵列中。该位点的遗传和表观遗传特征促进了从头超级增强子样元件的形成，以驱动高病毒癌基因表达。这提供了对超级增强子样元件的发生的深入了解，并且是HPV整合可以促进肿瘤发生的新机制。
Integration of human papillomavirus (HPV) genomes into cellular chromatin is common in HPV-associated cancers. Integration is random, and each site is unique depending on how and where the virus integrates. We recently showed that tandemly integrated HPV16 could result in the formation of a super-enhancer-like element that drives transcription of the viral oncogenes. Here, we characterize the chromatin landscape and genomic architecture of this integration locus to elucidate the mechanisms that promoted de novo super-enhancer formation. Using next-generation sequencing and molecular combing/fiber-FISH, we show that ~26 copies of HPV16 are integrated into an intergenic region of chromosome 2p23.2, interspersed with 25 kb of amplified, flanking cellular DNA. This interspersed, co-amplified viral-host pattern is frequent in HPV-associated cancers and here we designate it as Type III integration. An abundant viral-cellular fusion transcript encoding the viral E6/E7 oncogenes is expressed from the integration locus and the chromatin encompassing both the viral enhancer and a region in the adjacent amplified cellular sequences is strongly enriched in the super-enhancer markers H3K27ac and Brd4. Notably, the peak in the amplified cellular sequence corresponds to an epithelial-cell-type specific enhancer. Thus, HPV16 integration generated a super-enhancer-like element composed of tandem interspersed copies of the viral upstream regulatory region and a cellular enhancer, to drive high levels of oncogene expression. Oncogenic human papillomavirus (HPV) infection is responsible for ~5% human cancers. A key event in the development of many of these cancers is integration of the viral genome into host chromatin. Integration results in dysregulated expression of the viral oncogenes, which promotes unregulated cellular division and the accumulation of cellular mutations, ultimately leading to cancer. Genetic rearrangement and/or amplification of cellular sequences flanking sites of integration are frequent in HPV positive tumors, and this can influence transcription of the viral oncogenes from integrated loci. We show an example where the HPV16 genome integrated adjacent to a cellular, tissue-specific enhancer and subsequently the viral DNA and flanking cellular sequences were co-amplified into a tandemly interspersed viral-cellular sequence array. The genetic and epigenetic signature of this site promoted the formation of a de novo super-enhancer-like element to drive high viral oncogene expression. This provides insight into the genesis of super-enhancer-like elements and is a novel mechanism by which HPV integration can promote oncogenesis.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
5.3
作者：
Holmes A;Lameiras S;Jeannot E;Marie Y;Castera L;Sastre-Garau X;Nicolas A
通讯作者：
Nicolas A
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
5.4
作者：
Fradet-Turcotte, Amelie;Bergeron-Labrecque, Fanny;Archambault, Jacques
通讯作者：
Archambault, Jacques