Recurrent integration of human papillomavirus genomes at transcriptional regulatory hubs.
Recurrent integration of human papillomavirus genomes at transcriptional regulatory hubs.
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DOI：
10.1038/s41525-021-00264-y
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发表时间：
2021-11-30
影响因子：
5.3
通讯作者：
McBride AA
中科院分区：
文献类型：
--
作者：
Warburton A;Markowitz TE;Katz JP;Pipas JM;McBride AA
在HPV相关癌症中，致癌性人乳头瘤病毒（HPV）基因组通常整合到宿主染色体中。HPV基因组作为病毒DNA的单拷贝或串联重复序列整合，其中散布或不散布宿主DNA。整合经常发生在对串联重复序列形成敏感的常见脆性位点，并且侧翼或散布的宿主DNA通常含有转录增强子元件。当与病毒基因组共扩增时，这些增强子可以形成驱动高病毒癌基因表达的超级增强子样元件。在这里，我们编辑了宫颈（CESC）和头颈部鳞状细胞癌（HNSCC）癌症中HPV整合位点的高度策划的数据集，并评估了每个插入位点的断点数量，病毒转录活性和宿主基因组拷贝数。肿瘤通常含有多个不同的HPV整合位点，但通常只有一个表达病毒RNA的“驱动”位点。由于常见的脆性位点和活性增强子元件是细胞类型特异性的，我们分别使用FANCD 2和Brd 4/H3 K27 ac ChIP-seq在宫颈细胞系中定位了这些区域。还使用Brd 4/H3 K27 ac ChIP-seq数据集定义了大增强子簇或超级增强子。HPV整合断裂点在FANCD 2相关脆性位点和增强子富集区富集，并且在CESC样品中经常显示邻近的局灶性DNA扩增。我们确定了经常性的整合“热点”，这些热点富含超级增强子，其中一些作为细胞身份基因的调控中心。我们认为，在持续感染，染色体外HPV微小染色体与这些转录中心和意外整合可能会促进病毒癌基因的表达和癌变。
Oncogenic human papillomavirus (HPV) genomes are often integrated into host chromosomes in HPV-associated cancers. HPV genomes are integrated either as a single copy or as tandem repeats of viral DNA interspersed with, or without, host DNA. Integration occurs frequently in common fragile sites susceptible to tandem repeat formation and the flanking or interspersed host DNA often contains transcriptional enhancer elements. When co-amplified with the viral genome, these enhancers can form super-enhancer-like elements that drive high viral oncogene expression. Here we compiled highly curated datasets of HPV integration sites in cervical (CESC) and head and neck squamous cell carcinoma (HNSCC) cancers, and assessed the number of breakpoints, viral transcriptional activity, and host genome copy number at each insertion site. Tumors frequently contained multiple distinct HPV integration sites but often only one “driver” site that expressed viral RNA. As common fragile sites and active enhancer elements are cell-type-specific, we mapped these regions in cervical cell lines using FANCD2 and Brd4/H3K27ac ChIP-seq, respectively. Large enhancer clusters, or super-enhancers, were also defined using the Brd4/H3K27ac ChIP-seq dataset. HPV integration breakpoints were enriched at both FANCD2-associated fragile sites and enhancer-rich regions, and frequently showed adjacent focal DNA amplification in CESC samples. We identified recurrent integration “hotspots” that were enriched for super-enhancers, some of which function as regulatory hubs for cell-identity genes. We propose that during persistent infection, extrachromosomal HPV minichromosomes associate with these transcriptional epicenters and accidental integration could promote viral oncogene expression and carcinogenesis.
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影响因子：
6.7
作者：
Groves IJ;Drane ELA;Michalski M;Monahan JM;Scarpini CG;Smith SP;Bussotti G;Várnai C;Schoenfelder S;Fraser P;Enright AJ;Coleman N
通讯作者：
Coleman N
DOI：
10.1093/bioinformatics/btv562
发表时间：
2016-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Gel B;Díez-Villanueva A;Serra E;Buschbeck M;Peinado MA;Malinverni R
通讯作者：
Malinverni R
影响因子：
21.3
作者：
Chan, Kok Lung;Palmai-Pallag, Timea;Hickson, Ian D.
通讯作者：
Hickson, Ian D.
影响因子：
16.6
作者：
Brison, Olivier;El-Hilali, Sami;Chen, Chun-Long
通讯作者：
Chen, Chun-Long
影响因子：
6.4
作者：
Chaiwongkot, Arkom;Vinokurova, Svetlana;Doeberitz, Magnus von Knebel
通讯作者：
Doeberitz, Magnus von Knebel