HPV-CCDC106 integration alters local chromosome architecture and hijacks an enhancer by three-dimensional genome structure remodeling in cervical cancer
HPV-CCDC106 integration alters local chromosome architecture and hijacks an enhancer by three-dimensional genome structure remodeling in cervical cancer
复制标题
HPV-CCDC106 整合改变了宫颈癌的局部染色体结构，并通过三维基因组结构重塑劫持了增强子。
DOI：
10.1016/j.jgg.2020.05.006
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发表时间：
2020-08-01
影响因子：
5.9
通讯作者：
Wu, Peng
中科院分区：
文献类型：
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作者：
Cao, Canhui;Hong, Ping;Wu, Peng
人乳头瘤病毒（HPV）DNA整合到人类基因组中被认为是宫颈癌的关键驱动因素。然而，HPV整合对染色质结构组织和基因表达的影响在很大程度上是未知的。我们研究了一组61个样本，并在19号染色体的CCDC106基因中确定了一个整合热点。然后我们选取了含有CCDC106独特整合位点且无HPV游离DNA的新鲜癌组织，并进行了全基因组、RNA、染色质免疫沉淀和高通量染色体构象捕获（Hi - C）测序，以确定HPV在宫颈癌发生中的整合机制。分子分析表明，19号染色体表现出显著的基因组变异和差异表达密度，并且在三维（3D）结构变化和基因表达之间发现了相关性。重要的是，HPV整合将一个拓扑相关结构域（TAD）分成两个更小的TAD，并从PEG3劫持了一个增强子到CCDC106，导致PEG3表达降低和CCDC106表达增加。我们用队列中的10个具有相同HPV - CCDC106整合的样本进一步证实了这种表达失调。总之，我们发现HPV - CCDC106整合改变了局部染色体结构，并通过3D基因组结构重塑劫持了一个增强子。因此，这项研究为HPV在宫颈癌发生中整合的3D结构机制提供了见解。版权所有（C）2020，作者。中国科学院遗传与发育生物学研究所，中国遗传学会。由爱思唯尔有限公司和科学出版社出版。
Integration of human papillomavirus (HPV) DNA into the human genome is a reputed key driver of cervical cancer. However, the effects of HPV integration on chromatin structural organization and gene expression are largely unknown. We studied a cohort of 61 samples and identified an integration hot spot in the CCDC106 gene on chromosome 19. We then selected fresh cancer tissue that contained the unique integration loci at CCDC106 with no HPV episomal DNA and performed whole-genome, RNA, chromatin immunoprecipitation and high-throughput chromosome conformation capture (Hi-C) sequencing to identify the mechanisms of HPV integration in cervical carcinogenesis. Molecular analyses indicated that chromosome 19 exhibited significant genomic variation and differential expression densities, with correlation found between three-dimensional (3D) structural change and gene expression. Importantly, HPV integration divided one topologically associated domain (TAD) into two smaller TADs and hijacked an enhancer from PEG3 to CCDC106, with a decrease in PEG3 expression and an increase in CCDC106 expression. This expression dysregulation was further confirmed using 10 samples from our cohort, which exhibited the same HPV-CCDC106 integration. In summary, we found that HPV-CCDC106 integration altered local chromosome architecture and hijacked an enhancer via 3D genome structure remodeling. Thus, this study provides insight into the 3D structural mechanism underlying HPV integration in cervical carcinogenesis. Copyright (C) 2020, The Authors. Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press.