Project description: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.
Project description:In organisms ranging from vertebrates to plants, major components of centromeres are rapidly-evolving repeat sequences, such as tandem repeats (TRs) and transposable elements (TEs). These repeats harbor centromere-specific histone H3 (CENH3), which also evolves rapidly. Complete centromere structures recently determined in human and Arabidopsis suggest frequent integration and purging of retrotransposons within the TR regions of centromeres. Despite the high impact of “centrophilic” retrotransposons on the paradox of rapid centromere evolution, the mechanisms involved in centromere targeting remain poorly understood in any organism. Here we show that both Ty3 and Ty1/Copia LTR elements rapidly turnover within the centromeric TRs of Arabidopsis species. We demonstrate that the Ty1/Copia element Tal1 (Transposon of Arabidopsis lyrata 1) integrates de novo into regions occupied by CENH3 in A. thaliana, and that ectopic expansion of the CENH3 region results in spread of Tal1 integration regions. The integration spectra of chimeric TEs revealed the key structural variations responsible for the contrasting chromatin targeting specificities to centromeres versus gene-rich regions, which have recurrently converted during the evolution of these TEs. Our findings reveal the impact of centromeric chromatin on TE-mediated rapid centromere evolution, with relevance across eukaryotic genomes.
Project description:In organisms ranging from vertebrates to plants, major components of centromeres are rapidly-evolving repeat sequences, such as tandem repeats (TRs) and transposable elements (TEs). These repeats harbor centromere-specific histone H3 (CENH3), which also evolves rapidly. Complete centromere structures recently determined in human and Arabidopsis suggest frequent integration and purging of retrotransposons within the TR regions of centromeres. Despite the high impact of “centrophilic” retrotransposons on the paradox of rapid centromere evolution, the mechanisms involved in centromere targeting remain poorly understood in any organism. Here we show that both Ty3 and Ty1/Copia LTR elements rapidly turnover within the centromeric TRs of Arabidopsis species. We demonstrate that the Ty1/Copia element Tal1 (Transposon of Arabidopsis lyrata 1) integrates de novo into regions occupied by CENH3 in A. thaliana, and that ectopic expansion of the CENH3 region results in spread of Tal1 integration regions. The integration spectra of chimeric TEs revealed the key structural variations responsible for the contrasting chromatin targeting specificities to centromeres versus gene-rich regions, which have recurrently converted during the evolution of these TEs. Our findings reveal the impact of centromeric chromatin on TE-mediated rapid centromere evolution, with relevance across eukaryotic genomes.
2024-08-08 | GSE263224 | GEO
Project description:Capture Seuencing of Tandem Repeats
Project description:An integral part of human cellular homeostasis substantially relies on defense transcriptional responses tailored to fight microbial pathogens, including Viruses. However, a definitive anatomy of the “virus-responsive” fates of the non-coding genome was largely elusive. Here, we exhaustively assayed the human transcriptome and epigenome under naïve and antiviral cellular states and defined remarkable reprogramming to mark the exchange of cellular fates, involving previously unspecified, unsupervised, or overlooked non-coding entities endowed with thousands of novel virus-responsive enhancers, Super-enhancers (SEs), and Repetitive DNA enhancers. These functional determinants demonstrate superior chromatin architecture, stimulus-specificity, and transcriptional fitness, and neighbor, reside proximal, or entirely coincide with hundreds of the virus-stimulated genes, while a multitude of those is bound by the master antimicrobial TFs, IRF3 or/and NFκB, upon cell infection. A plethora of these DNA elements is traced within the repetitive fate of the human genome including Simple Tandem Repeats (STRs), Dispersed Repeats (DRs) such as retrotransposons and DNA transposons, and chimeras of those, enriched in HCTFBSs recognized by IRF3 or/and NFκB and exhibits pervasive imprints in the genomes of evolutionary recent, old and ancient species, including viruses. These findings emphasize the role of the architectural and functional compartmentalization of the human epigenome in naïve and infected cells on the perplexing natural conflicts and mechanistic dependencies that impose the frontage of defense gene expression in humans.
Project description:An integral part of human cellular homeostasis substantially relies on defense transcriptional responses tailored to fight microbial pathogens, including Viruses. However, a definitive anatomy of the “virus-responsive” fates of the non-coding genome was largely elusive. Here, we exhaustively assayed the human transcriptome and epigenome under naïve and antiviral cellular states and defined remarkable reprogramming to mark the exchange of cellular fates, involving previously unspecified, unsupervised, or overlooked non-coding entities endowed with thousands of novel virus-responsive enhancers, Super-enhancers (SEs), and Repetitive DNA enhancers. These functional determinants demonstrate superior chromatin architecture, stimulus-specificity, and transcriptional fitness, and neighbor, reside proximal, or entirely coincide with hundreds of the virus-stimulated genes, while a multitude of those is bound by the master antimicrobial TFs, IRF3 or/and NFκB, upon cell infection. A plethora of these DNA elements is traced within the repetitive fate of the human genome including Simple Tandem Repeats (STRs), Dispersed Repeats (DRs) such as retrotransposons and DNA transposons, and chimeras of those, enriched in HCTFBSs recognized by IRF3 or/and NFκB and exhibits pervasive imprints in the genomes of evolutionary recent, old and ancient species, including viruses. These findings emphasize the role of the architectural and functional compartmentalization of the human epigenome in naïve and infected cells on the perplexing natural conflicts and mechanistic dependencies that impose the frontage of defense gene expression in humans.
Project description:An integral part of human cellular homeostasis substantially relies on defense transcriptional responses tailored to fight microbial pathogens, including Viruses. However, a definitive anatomy of the “virus-responsive” fates of the non-coding genome was largely elusive. Here, we exhaustively assayed the human transcriptome and epigenome under naïve and antiviral cellular states and defined remarkable reprogramming to mark the exchange of cellular fates, involving previously unspecified, unsupervised, or overlooked non-coding entities endowed with thousands of novel virus-responsive enhancers, Super-enhancers (SEs), and Repetitive DNA enhancers. These functional determinants demonstrate superior chromatin architecture, stimulus-specificity, and transcriptional fitness, and neighbor, reside proximal, or entirely coincide with hundreds of the virus-stimulated genes, while a multitude of those is bound by the master antimicrobial TFs, IRF3 or/and NFκB, upon cell infection. A plethora of these DNA elements is traced within the repetitive fate of the human genome including Simple Tandem Repeats (STRs), Dispersed Repeats (DRs) such as retrotransposons and DNA transposons, and chimeras of those, enriched in HCTFBSs recognized by IRF3 or/and NFκB and exhibits pervasive imprints in the genomes of evolutionary recent, old and ancient species, including viruses. These findings emphasize the role of the architectural and functional compartmentalization of the human epigenome in naïve and infected cells on the perplexing natural conflicts and mechanistic dependencies that impose the frontage of defense gene expression in humans.
Project description:An integral part of human cellular homeostasis substantially relies on defense transcriptional responses tailored to fight microbial pathogens, including Viruses. However, a definitive anatomy of the “virus-responsive” fates of the non-coding genome was largely elusive. Here, we exhaustively assayed the human transcriptome and epigenome under naïve and antiviral cellular states and defined remarkable reprogramming to mark the exchange of cellular fates, involving previously unspecified, unsupervised, or overlooked non-coding entities endowed with thousands of novel virus-responsive enhancers, Super-enhancers (SEs), and Repetitive DNA enhancers. These functional determinants demonstrate superior chromatin architecture, stimulus-specificity, and transcriptional fitness, and neighbor, reside proximal, or entirely coincide with hundreds of the virus-stimulated genes, while a multitude of those is bound by the master antimicrobial TFs, IRF3 or/and NFκB, upon cell infection. A plethora of these DNA elements is traced within the repetitive fate of the human genome including Simple Tandem Repeats (STRs), Dispersed Repeats (DRs) such as retrotransposons and DNA transposons, and chimeras of those, enriched in HCTFBSs recognized by IRF3 or/and NFκB and exhibits pervasive imprints in the genomes of evolutionary recent, old and ancient species, including viruses. These findings emphasize the role of the architectural and functional compartmentalization of the human epigenome in naïve and infected cells on the perplexing natural conflicts and mechanistic dependencies that impose the frontage of defense gene expression in humans.
Project description:An integral part of human cellular homeostasis substantially relies on defense transcriptional responses tailored to fight microbial pathogens, including Viruses. However, a definitive anatomy of the “virus-responsive” fates of the non-coding genome was largely elusive. Here, we exhaustively assayed the human transcriptome and epigenome under naïve and antiviral cellular states and defined remarkable reprogramming to mark the exchange of cellular fates, involving previously unspecified, unsupervised, or overlooked non-coding entities endowed with thousands of novel virus-responsive enhancers, Super-enhancers (SEs), and Repetitive DNA enhancers. These functional determinants demonstrate superior chromatin architecture, stimulus-specificity, and transcriptional fitness, and neighbor, reside proximal, or entirely coincide with hundreds of the virus-stimulated genes, while a multitude of those is bound by the master antimicrobial TFs, IRF3 or/and NFκB, upon cell infection. A plethora of these DNA elements is traced within the repetitive fate of the human genome including Simple Tandem Repeats (STRs), Dispersed Repeats (DRs) such as retrotransposons and DNA transposons, and chimeras of those, enriched in HCTFBSs recognized by IRF3 or/and NFκB and exhibits pervasive imprints in the genomes of evolutionary recent, old and ancient species, including viruses. These findings emphasize the role of the architectural and functional compartmentalization of the human epigenome in naïve and infected cells on the perplexing natural conflicts and mechanistic dependencies that impose the frontage of defense gene expression in humans.
2025-02-24 | GSE288595 | GEO
Project description:Genome Scanning for Short Tandem Repeats