Structural Variations of the 3D Genome Architecture in Cervical Cancer Development

Abstract

Human papillomavirus (HPV) integration is the major contributor to cervical cancer (CC) development by inducing structural variations (SVs) in the human genome. SVs are directly associated with the three-dimensional (3D) genome structure leading to cancer development. The detection of SVs is not a trivial task, and several genome-wide techniques have greatly helped in the identification of SVs in the cancerous genome. However, in cervical cancer, precise prediction of SVs mainly translocations and their effects on 3D-genome and gene expression still need to be explored. Here, we have used high-throughput chromosome conformation capture (Hi-C) data of cervical cancer to detect the SVs, especially the translocations, and validated it through whole-genome sequencing (WGS) data. We found that the cervical cancer 3D-genome architecture rearranges itself as compared to that in the normal tissue, and 24% of the total genome switches their A/B compartments. Moreover, translocation detection from Hi-C data showed the presence of high-resolution t(4;7) (q13.1; q31.32) and t(1;16) (q21.2; q22.1) translocations, which disrupted the expression of the genes located at and nearby positions. Enrichment analysis suggested that the disrupted genes were mainly involved in controlling cervical cancer-related pathways. In summary, we detect the novel SVs through Hi-C data and unfold the association among genome-reorganization, translocations, and gene expression regulation. The results help understand the underlying pathogenicity mechanism of SVs in cervical cancer development and identify the targeted therapeutics against cervical cancer.

HPV16-LINC00393 Integration Alters Local 3D Genome Architecture in Cervical Cancer Cells

“…To study these chromatin interactions, the combination of multiple capture assays such as Hi-C, assay of transposase accessible chromatin sequencing (ATAC-seq) (Wang et al, 2020), whole-genome sequencing (WGS) (Adeel et al, 2021), RNA sequencing (RNA-seq) and/ or chromatin immunoprecipitation sequencing (ChIP-seq) (Zhang et al, 2020) has been developed. Up to date, several studies have characterized the structural variations of HPV-driven cervical cancer within certain integration hot spots (Cao et al, 2020), or by examining the genome-wide interactions using more unbiased approaches (Adeel et al, 2021;Groves et al, 2021). Investigating chromatin structure in cancer has the potential to identify candidate biomarkers, since the organization of the chromatin is often disturbed in cancer (Barutcu et al, 2015).…”

“…Moreover, genes are most often regulated by enhancers located within the same TAD. To study these chromatin interactions, the combination of multiple capture assays such as Hi-C, assay of transposase accessible chromatin sequencing (ATAC-seq) ( Wang et al., 2020 ), whole-genome sequencing (WGS) ( Adeel et al., 2021 ), RNA sequencing (RNA-seq) and/or chromatin immunoprecipitation sequencing (ChIP-seq) ( Zhang et al., 2020 ) has been developed.…”

“…Up to date, several studies have characterized the structural variations of HPV-driven cervical cancer within certain integration hot spots ( Cao et al., 2020 ), or by examining the genome-wide interactions using more unbiased approaches ( Adeel et al., 2021 ; Groves et al., 2021 ). Investigating chromatin structure in cancer has the potential to identify candidate biomarkers, since the organization of the chromatin is often disturbed in cancer ( Barutcu et al., 2015 ).…”

Molecular Mechanisms of lncRNAs in the Dependent Regulation of Cancer and Their Potential Therapeutic Use

“…However, they are deregulated in many human cancers. Along with them, lncRNAs derived from the transcription of active enhancers are differentially expressed in cancer tissues and have been revealed to act as oncogenes, promoting the transcriptional activation of the oncogenic pathways and even inducing chromosomal rearrangements and genomic instability [ 115 , 116 , 117 , 118 ].…”

Editorial: Bioinformatics of Genome Regulation, Volume I

“…Arega et al presented a novel tool for 3D genomics modeling of long-range chromatin interactions, the ChIAMM algorithm, which utilizes ChIA-PET (Chromatin Interaction Analysis by Paired-End Tags sequencing) to estimate amounts of chromosome contacts (loops) mediated by a given transcription factor. The same authors’ group has also described a 3D genome structure in cervical cancer cells ( Adeel et al, 2021 ). The topic of genome architecture prediction based on 3D interaction maps in cell nuclei was further advanced by Belokopytova and Fishman .…”