Short- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis.
Short- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis.
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DOI：
10.1371/journal.ppat.1009875
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发表时间：
2021-08
期刊：
影响因子：
6.7
通讯作者：
Coleman N
中科院分区：
文献类型：
--
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
宫颈癌的发生与人乳头瘤病毒（HPV）基因组整合到宿主染色体以及随后的HPV癌基因表达调控直接相关，这与整合HPV基因组的多层表观遗传变化相关。然而，在我们的HPV16整合克隆自然选择模型中，整合本身和整合位点宿主基因表达失调的过程仍然是一个谜。我们现在展示，使用最先进的“HPV整合位点捕获”（HISC）技术，整合可能通过微同源介导的修复（MHMR）机制发生，通过直接过程，导致宿主序列缺失（在我们的情况下，部分纯合）或通过“循环”机制，通过侧翼宿主区域被放大。此外，利用我们的“hpv16特异性区域捕获Hi-C”技术，我们已经确定，整合病毒基因组和宿主染色体之间的染色质相互作用，无论是在短（<500 kbp）还是长（>500 kbp），似乎都通过破坏宿主来驱动局部宿主基因失调：宿主相互作用在（但不超过）被称为拓扑相关结构域（TADs）的宿主结构内。HPV诱导宿主基因表达调节的这一机制表明，在“致癌基因”附近或内部整合病毒基因组对影响其表达并不必要，这些基因组相互作用的修饰可能在宫颈肿瘤进展的早期阶段选择HPV整合物中起主要作用。人乳头瘤病毒（hpv）与宿主染色体的整合是hpv相关癌症的一个主要特征，然而，这种整合发生的过程以及随后驱动癌变的过程尚不完全清楚。在这里，我们设计了一种最先进的HPV16基因组特异性DNA捕获技术，以核苷酸分辨率精确确定宿主整合位点，从而我们确认了HPV16基因组“直接”和“循环”整合到宿主中的微同源介导修复（MHMR）机制。此外，我们的技术检测到病毒整合后HPV16与宿主染色质之间的短期和长期相互作用，这与距离整合位点高达500kbp的宿主基因表达失调有关。这意味着HPV16基因组可以直接影响宿主染色体上远比最初认为的更远的宿主基因表达，这可能导致某些整合克隆的竞争生长优势。因此，我们的研究为乳头瘤病毒在HPV整合后早期启动和驱动宫颈癌发生的机制提供了进一步的见解。
Development of cervical cancer is directly associated with integration of human papillomavirus (HPV) genomes into host chromosomes and subsequent modulation of HPV oncogene expression, which correlates with multi-layered epigenetic changes at the integrated HPV genomes. However, the process of integration itself and dysregulation of host gene expression at sites of integration in our model of HPV16 integrant clone natural selection has remained enigmatic. We now show, using a state-of-the-art ‘HPV integrated site capture’ (HISC) technique, that integration likely occurs through microhomology-mediated repair (MHMR) mechanisms via either a direct process, resulting in host sequence deletion (in our case, partially homozygously) or via a ‘looping’ mechanism by which flanking host regions become amplified. Furthermore, using our ‘HPV16-specific Region Capture Hi-C’ technique, we have determined that chromatin interactions between the integrated virus genome and host chromosomes, both at short- (<500 kbp) and long-range (>500 kbp), appear to drive local host gene dysregulation through the disruption of host:host interactions within (but not exceeding) host structures known as topologically associating domains (TADs). This mechanism of HPV-induced host gene expression modulation indicates that integration of virus genomes near to or within a ‘cancer-causing gene’ is not essential to influence their expression and that these modifications to genome interactions could have a major role in selection of HPV integrants at the early stage of cervical neoplastic progression. The integration of human papillomaviruses (HPVs) into host chromosomes is a major feature of HPV-associated cancers, however the process by which this occurs and subsequently drives carcinogenesis is incompletely understood. Here, we devised a state-of-the-art HPV16 genome-specific DNA capture technology to precisely determine the host integration sites at a nucleotide resolution, such that we confirm the mechanism of microhomology-mediated repair (MHMR) during both ‘direct’ and ‘looping’ integration of HPV16 genomes into the host. Furthermore, our technology detects both short- and long-range interactions between HPV16 and host chromatin after virus integration, which correlates with dysregulation of host gene expression at distances up to 500kbp from the integration site. This means that HPV16 genomes can directly affect host gene expression much further away on host chromosomes than initially thought, which may lead to competitive growth advantages for certain integrated clones. Therefore, our study provides further insight into the mechanisms by which papillomaviruses are able to initiate and drive cervical carcinogenesis at an early stage after HPV integration.
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胰腺癌预后 miRNA 特征和潜在关键基因的生物信息学分析。
影响因子：
4.7
作者：
Chen S;Gao C;Yu T;Qu Y;Xiao GG;Huang Z
通讯作者：
Huang Z
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
7
作者：
Dryden NH;Broome LR;Dudbridge F;Johnson N;Orr N;Schoenfelder S;Nagano T;Andrews S;Wingett S;Kozarewa I;Assiotis I;Fenwick K;Maguire SL;Campbell J;Natrajan R;Lambros M;Perrakis E;Ashworth A;Fraser P;Fletcher O
通讯作者：
Fletcher O
影响因子：
5.4
作者：
BEDELL, MA;HUDSON, JB;LAIMINS, LA
通讯作者：
LAIMINS, LA
影响因子：
5.9
作者：
Cook, Lucy;Melamed, Anat;Bangham, Charles R. M.
通讯作者：
Bangham, Charles R. M.