Accession	GSE183048
Status	2021/9/1
Title	Recurrent Integration of Human Papillomavirus Genomes at Transcriptional Regulatory Hubs
Organism	Homo sapiens
Experiment type	Genome binding/occupancy profiling by high throughput sequencing
Summary	Oncogenic human papillomavirus (HPV) genomes are often integrated into host chromosomes in HPV-associated cancers. HPV genomes are integrated either as a single copy, or as tandem repeats of viral DNA interspersed with, or without, host DNA. Integration occurs frequently in common fragile sites susceptible to tandem repeat formation, and the flanking or interspersed host DNA often contains transcriptional enhancer elements. When co-amplified with the viral genome, these enhancers can form super-enhancer-like elements that drive high viral oncogene expression. Here, we compiled highly curated datasets of HPV integration sites in cervical (CESC) and head and neck squamous cell carcinoma (HNSCC) cancers and assessed the number of breakpoints, viral transcriptional activity, and host genome copy number at each insertion site. Tumors frequently contained multiple distinct HPV integration sites, but often only one “driver” site that expressed viral RNA. Since common fragile sites and active enhancer elements are cell-type specific, we mapped these regions in cervical cell lines using FANCD2 and Brd4/H3K27ac ChIP-seq, respectively. Large enhancer clusters, or super-enhancers, were also defined using the Brd4/H3K27ac ChIP-seq dataset. HPV integration breakpoints were enriched at both FANCD2-associated fragile sites, and enhancer-rich regions, and frequently showed adjacent focal DNA amplification in CESC samples. We identified recurrent integration “hotspots” that were enriched for super-enhancers, some of which function as regulatory hubs for cell-identity genes. We propose that during persistent infection, extrachromosomal HPV minichromosomes associate with these transcriptional epicenters, and accidental integration could promote viral oncogene expression and carcinogenesis.
Samples	GSM ID Sample info Characteristics Description GSM5550295 C33-A cells - FANCD2 cell type:HPV negative cervical carcinoma cells; cell line:C33-A; chip-seq antibody:FANCD2 (Bethyl, A302-174A, lot 1); treatment:24 hour 0.2 uM aphidicolin treatment Processed data files normalised to """"C33-A cells - input DNA GSM5550296 C33-A cells - input DNA cell type:HPV negative cervical carcinoma cells; cell line:C33-A; chip-seq antibody:None; treatment:24 hour 0.2 uM aphidicolin treatment - GSM5550297 HeLa cells - FANCD2 cell type:Integrated HPV18 positive cervical carcinoma cells; cell line:HeLa; chip-seq antibody:FANCD2 (Bethyl, A302-174A, lot 1); treatment:24 hour 0.2 uM aphidicolin treatment Processed data files normalised to """"HeLa cells - input DNA GSM5550298 HeLa cells - input DNA cell type:Integrated HPV18 positive cervical carcinoma cells; cell line:HeLa; chip-seq antibody:None; treatment:24 hour 0.2 uM aphidicolin treatment - GSM5550299 W12 cells - Brd4_rep1 cell type:Integrated HPV16 positive cervical keratinocytes; cell line:W12-20831; chip-seq antibody:Brd4 (Bethyl, A301-985A, lot 5); treatment:Untreated Processed data files normalised to """"W12 cells - input DNA_20831_rep1 GSM5550300 W12 cells - Brd4_rep2 cell type:Integrated HPV16 positive cervical keratinocytes; cell line:W12-20831; chip-seq antibody:Brd4 (Bethyl, A301-985A, lot 5); treatment:Untreated Processed data files normalised to """"W12 cells - input DNA_20831_rep1 GSM5550301 W12 cells - Brd4_rep3 cell type:Integrated HPV16 positive cervical keratinocytes; cell line:W12-20861; chip-seq antibody:Brd4 (Bethyl, A301-985A, lot 5); treatment:Untreated Processed data files normalised to """"W12 cells - input DNA_20861_rep2 GSM5550302 W12 cells - Brd4_rep4 cell type:Integrated HPV16 positive cervical keratinocytes; cell line:W12-20861; chip-seq antibody:Brd4 (Bethyl, A301-985A, lot 5); treatment:Untreated Processed data files normalised to """"W12 cells - input DNA_20861_rep2 GSM5550303 W12 cells - Brd4_rep5 cell type:Integrated HPV16 positive cervical keratinocytes; cell line:W12-20862; chip-seq antibody:Brd4 (Bethyl, A301-985A, lot 5); treatment:Untreated Processed data files normalised to """"W12 cells - input DNA_20862_rep3 GSM5550304 W12 cells - Brd4_rep6 cell type:Integrated HPV16 positive cervical keratinocytes; cell line:W12-20862; chip-seq antibody:Brd4 (Bethyl, A301-985A, lot 5); treatment:Untreated Processed data files normalised to """"W12 cells - input DNA_20862_rep3 GSM5550305 W12 cells - Brd4_rep7 cell type:Extrachromosomal HPV16 positive cervical keratinocytes; cell line:W12-20863; chip-seq antibody:Brd4 (Bethyl, A301-985A, lot 5); treatment:Untreated Processed data files normalised to """"W12 cells - input DNA_20863_rep4 GSM5550306 W12 cells - Brd4_rep8 cell type:Extrachromosomal HPV16 positive cervical keratinocytes; cell line:W12-20863; chip-seq antibody:Brd4 (Bethyl, A301-985A, lot 5); treatment:Untreated Processed data files normalised to """"W12 cells - input DNA_20863_rep4 GSM5550307 W12 cells - H3K27ac_rep1 cell type:Integrated HPV16 positive cervical keratinocytes; cell line:W12-20831; chip-seq antibody:H3K27ac (Millipore, 07-360, lot 2762292); treatment:Untreated Processed data files normalised to """"W12 cells - input DNA_20831_rep1 GSM5550308 W12 cells - H3K27ac_rep2 cell type:Integrated HPV16 positive cervical keratinocytes; cell line:W12-20831; chip-seq antibody:H3K27ac (Millipore, 07-360, lot 2762292); treatment:Untreated Processed data files normalised to """"W12 cells - input DNA_20831_rep1 GSM5550309 W12 cells - H3K27ac_rep3 cell type:Integrated HPV16 positive cervical keratinocytes; cell line:W12-20861; chip-seq antibody:H3K27ac (Millipore, 07-360, lot 2762292); treatment:Untreated Processed data files normalised to """"W12 cells - input DNA_20861_rep2 GSM5550310 W12 cells - H3K27ac_rep4 cell type:Integrated HPV16 positive cervical keratinocytes; cell line:W12-20861; chip-seq antibody:H3K27ac (Millipore, 07-360, lot 2762292); treatment:Untreated Processed data files normalised to """"W12 cells - input DNA_20861_rep2 GSM5550311 W12 cells - H3K27ac_rep5 cell type:Integrated HPV16 positive cervical keratinocytes; cell line:W12-20862; chip-seq antibody:H3K27ac (Millipore, 07-360, lot 2762292); treatment:Untreated Processed data files normalised to """"W12 cells - input DNA_20862_rep3 GSM5550312 W12 cells - H3K27ac_rep6 cell type:Integrated HPV16 positive cervical keratinocytes; cell line:W12-20862; chip-seq antibody:H3K27ac (Millipore, 07-360, lot 2762292); treatment:Untreated Processed data files normalised to """"W12 cells - input DNA_20862_rep3 GSM5550313 W12 cells - H3K27ac_rep7 cell type:Extrachromosomal HPV16 positive cervical keratinocytes; cell line:W12-20863; chip-seq antibody:H3K27ac (Millipore, 07-360, lot 2762292); treatment:Untreated Processed data files normalised to """"W12 cells - input DNA_20863_rep4 GSM5550314 W12 cells - H3K27ac_rep8 cell type:Extrachromosomal HPV16 positive cervical keratinocytes; cell line:W12-20863; chip-seq antibody:H3K27ac (Millipore, 07-360, lot 2762292); treatment:Untreated Processed data files normalised to """"W12 cells - input DNA_20863_rep4 GSM5550315 W12 cells - input DNA_20831_rep1 cell type:Integrated HPV16 positive cervical keratinocytes; cell line:W12-20831; chip-seq antibody:None; treatment:Untreated - GSM5550316 W12 cells - input DNA_20861_rep2 cell type:Integrated HPV16 positive cervical keratinocytes; cell line:W12-20861; chip-seq antibody:None; treatment:Untreated - GSM5550317 W12 cells - input DNA_20862_rep3 cell type:Integrated HPV16 positive cervical keratinocytes; cell line:W12-20862; chip-seq antibody:None; treatment:Untreated - GSM5550318 W12 cells - input DNA_20863_rep4 cell type:Extrachromosomal HPV16 positive cervical keratinocytes; cell line:W12-20863; chip-seq antibody:None; treatment:Untreated -
Platform	GPL20301  : Illumina HiSeq 4000 (Homo sapiens)
Literature	34848725
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