HPV-CCDC106 integration alters local chromosome architecture and hijacks an enhancer by three-dimens

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Canhui Caoa, b, 1,
Ping Hongc, d, 1,
Xingyu Huangc, d, 1,
Da Line, f, g,
Gang Caoe, f, g,
Liming Wanga, b,
Bei Fenga, h,
Ping Wua, b,
Hui Shena, b,
Qian Xuc, d,
Ci Rena, b,
Yifan Menga, b,
Wenhua Zhia, b,
Ruidi Yua, b,
Juncheng Weia, b,
Wencheng Dinga, b,
Xun Tiani,
Qinghua Zhangi,
Wei Lia, b,
Qinglei Gaoa, b,
Gang Chena, b,
Kezhen Lia, b,
Wing-Kin Sungd, j,
Zheng Hub, k ,
Hui Wanga, b ,
Guoliang Lic, d ,
Peng Wua, b
aDepartment of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
bCancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
cNational Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, Wuhan, 430070, China
dAgricultural Bioinformatics Key Laboratory of Hubei Province, Hubei Engineering Technology Research Center of Agricultural Big Data, College of Informatics, Huazhong Agricultural University, Wuhan, 430070, China
eState Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China
fBio-Medical Center, Huazhong Agricultural University, Wuhan, 430070, China
gCollege of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
hDepartment of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
iDepartment of Obstetrics and Gynecology, Key Laboratory for Molecular Diagnosis of Hubei Province, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430010, China
jDepartment of Computational and Systems Biology, Genome Institute of Singapore, Singapore
kDepartment of Gynecological Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China

More InformationCorresponding author: E-mail address: huzheng1998@163.com (Zheng Hu);E-mail address: wang71hui@aliyun.com (Hui Wang);E-mail address: guoliang.li@mail.hzau.edu.cn (Guoliang Li);E-mail address: pengwu8626@tjh.tjmu.edu.cn (Peng Wu)
Publish Date:2020-08-25

Abstract

Abstract

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.
Keywords: Cervical cancer,
HPV integration,
Fusion gene,
Hi-C,
Enhancer,
TAD

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http://www.jgenetgenomics.org/article/exportPdf?id=70741953-1ca1-4f4a-ad2f-da5f0410848d&language=en