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Abstract
High-risk human papillomavirus (hrHPV) infection and integration were considered as essential onset factors for the development of cervical cancer. However, the mechanism on how hrHPV integration influences the host genome structure remains not fully understood. In this study, we performed in situ high-throughput chromosome conformation capture (Hi-C) sequencing, chromatin immunoprecipitation and sequencing (ChIP-seq), and RNA-sequencing (RNA-seq) in two cervical cells, 1) NHEK normal human epidermal keratinocyte; and 2) HPV16-integrated SiHa tumorigenic cervical cancer cells. Our results reveal that the HPV-LINC00393 integrated chromosome 13 exhibited significant genomic variation and differential gene expression, which was verified by calibrated CTCF and H3K27ac ChIP-Seq chromatin restructuring. Importantly, HPV16 integration led to differential responses in topologically associated domain (TAD) boundaries, with a decrease in the tumor suppressor KLF12 expression downstream of LINC00393. Overall, this study provides significant insight into the understanding of HPV16 integration induced 3D structural changes and their contributions on tumorigenesis, which supplements the theory basis for the cervical carcinogenic mechanism of HPV16 integration.
Highlights
Cervical cancer is the second most common type of cancer in women worldwide with nearly 604,000 new cases diagnosed and 342,000 deaths in 2020 (Sung et al, 2021)
Previous studies have mostly analyzed the impact of HPV integration on the onedimensional structure (Kadaja et al, 2009; Matovina et al, 2009) rather than three-dimensional structure
Our study combines High-Throughput Chromosome Conformation Capture (Hi-C)-seq, ChIP-seq and RNA sequencing (RNA-seq) to investigate the changes in 3D structure of HPV16 integrated SiHa cells
Summary
Cervical cancer is the second most common type of cancer in women worldwide with nearly 604,000 new cases diagnosed and 342,000 deaths in 2020 (Sung et al, 2021). High-risk human papillomaviruses (hrHPVs) such as HPV16, 18, and 31 were recognized as the essential factors to trigger tumorigenesis (Xia et al, 2017). Of these hrHPVs, HPV16 is responsible for approximately 50% of cervical cancer cases (Franceschi, 2021). The integration of HPV may cause chromosome instability and induce gene rearrangement and copy number variation (Duensing and Münger, 2004; PETT et al, 2004)
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