Tridimensional infiltration of DNA viruses into the host genome shows preferential contact with active chromatin

Moreau, Pierrick; Cournac, Axel; Palumbo, G.A.; Marbouty, Martial; Mortaza, Shogofa; Thierry, Agnès; Cairo, Stefano; Lavigne, Marc; Koszul, Romain; Neuveut, Christine

doi:10.1038/s41467-018-06739-4

Cited by 62 publications

(83 citation statements)

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“…Overall, it is likely that the three-dimensional host genome architecture around the vDNA affects the transcriptional output from the viral genome. This notion is in line with a recent Hi-C and vDNA capture analysis of AdV-C5-infected human hepatocytes where the viral genome preferentially interacted with transcription start sites and enhancers of active cellular genes, including genes that are upregulated during infection [106]. Since the Hi-C measurements are population-averaged snapshots and do not give information on the dynamics of the contacts, it is unknown whether AdV usurps enhancers of cellular genes to promote its transcription in addition to its own enhancers, or whether the viral enhancers create transcriptional hubs that benefit nearby cellular genes.…”

Section: Variable Transcription and Replication Activities Of Viral Gsupporting

confidence: 81%

Cell-to-cell and genome-to-genome variability of Adenovirus transcription tuned by the cell cycle

Suomalainen

Prasad

Kannan

et al. 2020

Preprint

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These authors contributed equally to this work. Abstract In clonal cultures, not all cells are equally susceptible to virus infection. Underlying mechanisms of infection variability are poorly understood. Here, we developed imagebased single cell measurements to scrutinize the heterogeneity of adenovirus (AdV) infection. AdV delivers, transcribes and replicates a linear double-stranded DNA genome in the nucleus. We measured the abundance of viral transcripts by singlemolecule RNA fluorescence in situ hybridization (FISH), and the incoming ethynyldeoxy-cytidine (EdC)-tagged viral genome by copper(I)-catalyzed azide-alkyne cycloaddition (click) reaction. The early transcripts increased from 2-12 hours, the late ones from 12-23 hours post infection (pi), indicating distinct accumulation kinetics. Surprisingly, the expression of the immediate early transactivator gene E1A only moderately correlated with the number of viral genomes in the cell nucleus, although the incoming viral DNA remained largely intact until 7 hours pi. Genome-to-genome heterogeneity was found at the level of viral transcription, as indicated by colocalization with the large intron containing early region E4 transcripts, uncorrelated to the multiplicity of incoming genomes in the nucleus. In accordance, individual genomes exhibited heterogeneous replication activity, as shown by single-strand DNA-FISH and immunocytochemistry. These results indicate that the variability in viral gene expression and replication are not due to defective genomes but due to host cell heterogeneity. By analyzing the cell cycle state, we found that G1 cells exhibited the highest E1A expression, and significantly increased the correlation between E1A expression and viral genome copy numbers. This combined imagebased single molecule procedure is ideally suited to explore the cell-to-cell variability in viral infection, including transcriptional activators and repressors, RNA splicing mechanisms, and the impact of the 3-dimensional nuclear topology on gene regulation. 3 Author SummaryAdenoviruses (AdV) are ubiquitous pathogens in vertebrates. They persist in infected people, and cause unpredictable outbreaks, morbidity and mortality across the globe.Here we report that the common human AdV type C5 (AdV-C5) gives rise to considerable infection variability at the level of single cells in culture, and that a major underlying reason is the cell-to-cell heterogeneity. By combining sensitive single molecule in situ technology for detecting the incoming viral DNA and newly synthesized viral transcripts we show that viral gene expression is heterogeneous between infected human cells, as well as individual genomes. We report a moderate correlation between the number of viral genomes in the nucleus and immediate early E1A transcripts. This correlation is increased in the G1 phase of the cell cycle, where the E1A transcripts were found to be more abundant than in any other cell cycle phase. Our results demonstrate the importance of cell-to-cell variability measurements for understand...

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Section: Variable Transcription and Replication Activities Of Viral Gsupporting

confidence: 81%

Cell-to-cell and genome-to-genome variability of Adenovirus transcription tuned by the cell cycle

Suomalainen

Prasad

Kannan

et al. 2020

Preprint

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“…In contrast, the integrated HBV DNA only expresses viral S antigen but is supposed to induce a diverse collection of genomic perturbations near viral integration sites, including direct gene disruption and viral promoter-driven host gene transcription. Although a recent study starts to explore viral DNA capture Hi-C to investigate the spatial nuclear organization of DNA 8 , the HBV DNA organization in human nuclear are still obscure due to the sensitivity of the detection method, especially the integrated HBV DNA.…”

Section: Introductionmentioning

confidence: 99%

“…a-d The proportions of HBV DNAs contact with different elements; violin and box plot represent the distribution of the proportions of random select reads (±3.5 kb around the Alu1 enzyme sites) overlapping with each element; point represents the proportions of HBV contact reads (±3.5 kb around the start site of the read) overlapping with each element. Top left violin inserts representing the random sample model followed the Ref 29. .…”

mentioning

confidence: 99%

3D landscape of Hepatitis B virus interactions with human chromatins

Yang

Jia

et al. 2020

Cell Discov

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Hepatitis B viral (HBV) DNAs, including covalently closed circular DNA (cccDNA) and integrated HBV DNA forms, are considered to be primary contributors to the development and progression of HBV-associated liver diseases. However, it remains largely unclear how HBV DNAs communicate with human chromatin. Here we employed a highly sensitive technology, 3C-high-throughput genome-wide translocation sequencing (3C-HTGTS), to globally identify HBV DNA–host DNA contacts in cellular models of HBV infection. HBV DNA does not randomly position in host genome but instead preferentially establishes contacts with the host DNA at active chromatin regions. HBV DNA–host DNA contacts are significantly enriched at H3K4me1-marked regions modified by KMT2C/D; this histone modification is also observed in the HBV cccDNA mini-chromosome and strongly influences HBV transcription. On the other hand, chromatin loop formed by integrated HBV DNA with host genomic DNA was found in transcriptionally active regions. Furthermore, HBV infection influences host gene expression accompanied with HBV DNA–host DNA contacts. Our study provides a 3D landscape of spatial organization of cccDNA and integrated HBV DNA within the human genome, which lays the foundation for a better understanding of the mechanisms how HBV involves in liver disease development and progression.

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“…Emerging evidence suggests that the host DNA damage response (DDR) pathways are also exploited by the polyomaviruses to support their gene expression, infection and pathogenic potential [ 123 , 124 , 125 , 126 ], though the specific roles of DDR components in these processes remain to be fully elucidated. In recent years, research on the three-dimensional chromosomal topology of several DNA viruses during infection has provided exciting new insight to suggest that viral episomal conformation may also play an important role in controlling viral gene expression, though polyomaviruses have yet to be studied in this context [ 127 , 128 , 129 , 130 ]. Therefore, this is an area of interest for future polyomavirus transcription research.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Regulation of Polyomavirus Transcription by Viral and Cellular Factors

Yang

You

2020

Viruses

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Polyomavirus infection is widespread in the human population. This family of viruses normally maintains latent infection within the host cell but can cause a range of human pathologies, especially in immunocompromised individuals. Among several known pathogenic human polyomaviruses, JC polyomavirus (JCPyV) has the potential to cause the demyelinating disease progressive multifocal leukoencephalopathy (PML); BK polyomavirus (BKPyV) can cause nephropathy in kidney transplant recipients, and Merkel cell polyomavirus (MCPyV) is associated with a highly aggressive form of skin cancer, Merkel cell carcinoma (MCC). While the mechanisms by which these viruses give rise to the relevant diseases are not well understood, it is clear that the control of gene expression in each polyomavirus plays an important role in determining the infectious tropism of the virus as well as their potential to promote disease progression. In this review, we discuss the mechanisms governing the transcriptional regulation of these pathogenic human polyomaviruses in addition to the best-studied simian vacuolating virus 40 (SV40). We highlight the roles of viral cis-acting DNA elements, encoded proteins and miRNAs that control the viral gene expression. We will also underline the cellular transcription factors and epigenetic modifications that regulate the gene expression of these viruses.

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Tridimensional infiltration of DNA viruses into the host genome shows preferential contact with active chromatin

Cited by 62 publications

References 62 publications

Cell-to-cell and genome-to-genome variability of Adenovirus transcription tuned by the cell cycle

Cell-to-cell and genome-to-genome variability of Adenovirus transcription tuned by the cell cycle

3D landscape of Hepatitis B virus interactions with human chromatins

Regulation of Polyomavirus Transcription by Viral and Cellular Factors

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