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HPV- CCDC106 Integration Alters Local Chromosome Architecture and Hijacks an Enhancer by Remodeling the 3D Genome Structure in Cervical Cancer

53 Pages Posted: 22 Nov 2019

See all articles by Canhui Cao

Canhui Cao

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

Ping Hong

HuaZhong Agricultural University

Xingyu Huang

HuaZhong Agricultural University

Da Lin

HuaZhong Agricultural University

Gang Cao

HuaZhong Agricultural University

Liming Wang

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

Bei Feng

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

Ping Wu

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

Hui Shen

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

Qian Xu

HuaZhong Agricultural University

Ci Ren

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

Yifan Meng

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

Wenhua Zhi

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

Ruidi Yu

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

Juncheng Wei

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

Wencheng Ding

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

Xun Tian

Huazhong University of Science and Technology (Formerly Tongi Medical University)

Qinghua Zhang

Huazhong University of Science and Technology (Formerly Tongi Medical University)

Wei Li

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

Xiaoyuan Huang

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

Gang Chen

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

Ling Xi

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Obstetrics and Gynecology

Junbo Hu

affiliation not provided to SSRN

Wing-Kin Sung

HuaZhong Agricultural University

Qinglei Gao

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Cancer Biology Research Center; Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Obstetrics and Gynecology

Zheng Hu

Sun Yat-Sen University (SYSU) - First Affiliated Hospital

Hui Wang

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

Guoliang Li

HuaZhong Agricultural University

Peng Wu

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Cancer Biology Research Center

More...

Abstract

Background: Integration of human papillomavirus (HPV) DNA into human genome is the reputed key driver of cervical cancer. However, the effects of HPV integration on chromatin structural organization and gene expression are largely unknown in such cancer.

Methods: We investigated a cohort of 61 samples for HPV integration analysis. And selected a fresh cancer tissue from the set of clinical samples whose tissue only contained unique integration loci at CCDC106 and contained no HPV episomal DNA. A combination of WGS, RNA-seq, ChIP-seq and Hi-C data analysis were applied to identify the mechanisms of HPV integration in cervical carcinogenesis. IHC staining was used to validate the expression change after HPV-CCDC106 integration.

Results: Based on the cohort of 61 samples, we identified a hot integrated site in the CCDC106 gene on chromosome 19. Additional analysis showed that this chromosome was enriched with genome variation and differential expression densities in the same HPV-CCDC106 integrated carcinoma sample. More importantly, we identified that HPV divided one topologically associated domain (TAD) into two TADs and hijacked an enhancer from PEG3 to CCDC106, thus leading to a decrease in PEG3 expression and high CCDC106 expression. This expression dysregulation was further confirmed by 10 samples exhibiting the same HPV-CCDC106 integration from our cohort.

Interpretation: We found that HPV-CCDC106 integration tended to alter the architecture of the local chromosome and hijacked an enhancer via 3D genome structure remodeling, thus providing insight into the 3D structural mechanism underlying HPV integration in cervical carcinogenesis.

Funding Statement: This work was supported by Natural Science Foundation of China (81630060 to P. W., 81830074 and 81772786 to H. W., 81572569 to G. C., 31771402 to G. L. and 81772775 to J. W.), National Science and Technology Major Project (2018ZX10301402-002 to Q. G.), and the research-oriented clinician funding program of Tongji Medical College, Huazhong University of Science and Technology for P.W.

Declaration of Interests: The authors declare no competing interests.

Ethics Approval Statement: All tumor specimens, ThinPrep cytologic test (TCT) samples, and normal cervical tissues were obtained from the Department of Gynecological Oncology at Tongji Hospital under ethics board approval (TJ-IRB20180611) and with documented informed consent from all patients.

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

Suggested Citation

Cao, Canhui and Hong, Ping and Huang, Xingyu and Lin, Da and Cao, Gang and Wang, Liming and Feng, Bei and Wu, Ping and Shen, Hui and Xu, Qian and Ren, Ci and Meng, Yifan and Zhi, Wenhua and Yu, Ruidi and Wei, Juncheng and Ding, Wencheng and Tian, Xun and Zhang, Qinghua and Li, Wei and Huang, Xiaoyuan and Chen, Gang and Xi, Ling and Hu, Junbo and Sung, Wing-Kin and Gao, Qinglei and Hu, Zheng and Wang, Hui and Li, Guoliang and Wu, Peng, HPV- CCDC106 Integration Alters Local Chromosome Architecture and Hijacks an Enhancer by Remodeling the 3D Genome Structure in Cervical Cancer (November 15, 2019). Available at SSRN: https://ssrn.com/abstract=3487700 or http://dx.doi.org/10.2139/ssrn.3487700

Canhui Cao

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

China

Ping Hong

HuaZhong Agricultural University

Wuhan, Hubei
Wuhan, Hubei 430070
China

Xingyu Huang

HuaZhong Agricultural University

Wuhan, Hubei
Wuhan, Hubei 430070
China

Da Lin

HuaZhong Agricultural University

Wuhan, Hubei
Wuhan, Hubei 430070
China

Gang Cao

HuaZhong Agricultural University

Wuhan, Hubei
Wuhan, Hubei 430070
China

Liming Wang

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

China

Bei Feng

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

China

Ping Wu

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

China

Hui Shen

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

China

Qian Xu

HuaZhong Agricultural University

Wuhan, Hubei
Wuhan, Hubei 430070
China

Ci Ren

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

China

Yifan Meng

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

China

Wenhua Zhi

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

China

Ruidi Yu

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

China

Juncheng Wei

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

China

Wencheng Ding

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

China

Xun Tian

Huazhong University of Science and Technology (Formerly Tongi Medical University) ( email )

1037 Luoyu Rd
Wuhan, Hubei 430074
China

Qinghua Zhang

Huazhong University of Science and Technology (Formerly Tongi Medical University)

Wuhan, Hubei
China

Wei Li

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

China

Xiaoyuan Huang

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

China

Gang Chen

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology

China

Ling Xi

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Obstetrics and Gynecology

China

Junbo Hu

affiliation not provided to SSRN

Wing-Kin Sung

HuaZhong Agricultural University

Wuhan, Hubei
Wuhan, Hubei 430070
China

Qinglei Gao

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Cancer Biology Research Center ( email )

Wuhan
China

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Obstetrics and Gynecology ( email )

China

Zheng Hu

Sun Yat-Sen University (SYSU) - First Affiliated Hospital ( email )

58th, Zhongshan 2nd road
Guangdong, 510080
China

Hui Wang

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Department of Gynecologic Oncology ( email )

China

Guoliang Li

HuaZhong Agricultural University ( email )

Wuhan, Hubei
Wuhan, Hubei 430070
China

Peng Wu (Contact Author)

Huazhong University of Science and Technology (Formerly Tongi Medical University) - Cancer Biology Research Center ( email )

Wuhan
China

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