HPV-CCDC106 integration alters local chromosome architecture and hijacks an enhancer by three-dimensional genome structure remodeling in cervical cancer

Canhui Cao; Ping Hong; Xingyu Huang; Da Lin; Gang Cao; Liming Wang; Bei Feng; Ping Wu; Hui Shen; Qian Xu; Ci Ren; Yifan Meng; Wenhua Zhi; Ruidi Yu; Juncheng Wei; Wencheng Ding; Xun Tian; Qinghua Zhang; Wei Li; Qinglei Gao; Gang Chen; Kezhen Li; Wing-Kin Sung; Zheng Hu; Hui Wang; Guoliang Li; Peng Wu

doi:10.1016/j.jgg.2020.05.006

Volume 47 Issue 8

Aug. 2020

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Article Navigation > Journal of Genetics and Genomics > 2020 > 47(8): 437-450

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HPV-CCDC106 integration alters local chromosome architecture and hijacks an enhancer by three-dimensional genome structure remodeling in cervical cancer

doi: 10.1016/j.jgg.2020.05.006

Canhui Cao^{a, b, 1},
Ping Hong^{c, d, 1},
Xingyu Huang^{c, d, 1},
Da Lin^{e, f, g},
Gang Cao^{e, f, g},
Liming Wang^{a, b},
Bei Feng^{a, h},
Ping Wu^{a, b},
Hui Shen^{a, b},
Qian Xu^{c, d},
Ci Ren^{a, b},
Yifan Meng^{a, b},
Wenhua Zhi^{a, b},
Ruidi Yu^{a, b},
Juncheng Wei^{a, b},
Wencheng Ding^{a, b},
Xun Tianⁱ,
Qinghua Zhangⁱ,
Wei Li^{a, b},
Qinglei Gao^{a, b},
Gang Chen^{a, b},
Kezhen Li^{a, b},
Wing-Kin Sung^{d, j},
Zheng Hu^{b, k},
Hui Wang^{a, b},
Guoliang Li^{c, d},
Peng Wu^{a, b}

a
Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
b
Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
c
National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, Wuhan, 430070, China
d
Agricultural Bioinformatics Key Laboratory of Hubei Province, Hubei Engineering Technology Research Center of Agricultural Big Data, College of Informatics, Huazhong Agricultural University, Wuhan, 430070, China
e
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China
f
Bio-Medical Center, Huazhong Agricultural University, Wuhan, 430070, China
g
College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
h
Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
i
Department 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
j
Department of Computational and Systems Biology, Genome Institute of Singapore, Singapore
k
Department of Gynecological Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China

More Information

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

These authors contributed equally to this work.

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References(65)

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