Epigenetic specifications of host chromosome docking sites for latent Epstein-Barr virus

Kim, Kyoung-Dong; Tanizawa, Hideki; Leo, Alessandra De; Vladimirova, Olga; Kossenkov, Andrew V.; Lü, Fang; Showe, Louise C.; Noma, Ken-ichi; Lieberman, Paul M.

doi:10.1038/s41467-019-14152-8

Cited by 57 publications

(90 citation statements)

References 69 publications

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“…For the visualization in Fig. 6 , supplementary Fig S6 , to get a more accurate view of the contacts, we also normalized the bias caused by restriction sites with 4C-ker 25 and the significant interaction was called like Kim et al 26 ; briefly, we called the significant interaction with bdgpeakcall subcommand form MACS2 27 (-c 20 -g 3000) and the consistent peak in #1 and #2 were used. The coloration analysis of histone markers and 3C-HTGTS data was performed by multiBigwigSummary 23 (BED-file) for each chromosome separately.…”

Section: Methodsmentioning

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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Section: Methodsmentioning

confidence: 99%

3D landscape of Hepatitis B virus interactions with human chromatins

Yang

Jia

et al. 2020

Cell Discov

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“…Recent studies using Hi-C methods examined EBV interactions with host chromosome in various cell types [40,52]. Another related study used capture Hi-C to analyze KSHV looping DNA interactions during latency and reactivation, and found that DNA loops organized around highly active RNA polymerase II promoters, especially that for the viral PAN non-coding RNA [53].…”

Section: Discussionmentioning

confidence: 99%

Structure-based mapping of the TβRI and TβRII receptor binding sites of the parasitic TGF-β mimic, Hp-TGM

Mukundan

Byeon

Hinck

et al. 2020

Preprint

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TGF-β is a secreted signaling protein involved in many physiological processes: organ development, production and maintenance of the extracellular matrix, as well as regulation of the adaptive immune system. As a cytokine, TGF-β stimulates the differentiation of CD4+ T-cells into regulatory T-cells (Tregs) that act to promote peripheral immune tolerance. The murine parasite Heligmosomoides polygyrus takes advantage of this pathway to induce inducing Foxp3+ Tregs in a similar manner using a TGF-β mimic (TGM), comprised of five tandem complement control protein (CCP) domains, designated D1-D5. Despite having no structural homology to TGF-β or to TGF-β family proteins, TGM binds directly to the TGF-β type I and type II receptors, TβRI and TβRII. To further investigate, NMR titration, and SPR and ITC binding experiments were performed, showing that TGM-D2, with the aid of D1, binds TβRI and TGM-D3 binds TβRII. Competition ITC experiments showed that TGM-D3 competes with TGF-β for binding to TβRII, consistent with TGM-D3-induced NMR chemical shift perturbations of TβRII which aligned with the solvent inaccessible areas of TβRII upon binding TGF-β. Thus, TGM-D3 binds to the same edged β-strand of TβRII that is used to bind TGF-β. Competition ITC experiments demonstrated that TGM-D1D2 and TGF-β3:TβRII compete for binding to TβRI, while TGM-D2-induced NMR chemical shift perturbation of TβRI showed that TGM-D2 binds to the same pre-helix extension of TβRI as does the TGF-β/TβRII binary complex. The solution structure of TGM-D3 revealed that while it has the overall structure of a CCP domain, TGM-D3 has an insertion in the hypervariable loop uncommon to CCP domains. These findings suggest that parasitic TGM, despite its lack of structural similarity to TGF-β, evolved to take advantage of the binding regions of the mammalian TGF-β type I and type II receptors. The structure of this TGM domain, along with the predicted structure of other H. polygyrus secreted proteins reported in the literature, suggest that TGM is part of a larger family of evolutionarily-adapted immunomodulatory CCP-containing proteins.

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“…4C-seq trans interactions were determined using a "window" method as described by Kim et al, (2020). Briefly, the virus viewpoint regions at the beginning of the reads were trimmed off using Cutadapt (Martin, 2011) software and the remaining human portions were aligned to the human UCSC hg38 reference genome using bowtie2 (version 2.3.5) (Langmead et al, 2009;Langmead and Salzberg, 2012).…”

Section: C-seq Analysismentioning

confidence: 99%

Higher-Order Chromatin Structures of Chromosomally Integrated HHV-6A Predict Integration Sites

Mariani

Zimmerman

Rodriguez

et al. 2021

Front. Cell. Infect. Microbiol.

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Human herpesvirus -6A and 6B (HHV-6A/B) can integrate their genomes into the telomeres of human chromosomes. Viral integration can occur in several cell types, including germinal cells, resulting in individuals that harbor the viral genome in every cell of their body. The integrated genome is efficiently silenced but can sporadically reactivate resulting in various clinical symptoms. To date, the integration mechanism and the subsequent silencing of HHV-6A/B genes remains poorly understood. Here we investigate the genome-wide chromatin contacts of the integrated HHV-6A in latently-infected cells. We show that HHV-6A becomes transcriptionally silent upon infection of these cells over the course of seven days. In addition, we established an HHV-6–specific 4C-seq approach, revealing that the HHV-6A 3D interactome is associated with quiescent chromatin states in cells harboring integrated virus. Furthermore, we observed that the majority of virus chromatin interactions occur toward the distal ends of specific human chromosomes. Exploiting this finding, we established a 4C-seq method that accurately detects the chromosomal integration sites. We further implement long-read minION sequencing in the 4C-seq assay and developed a method to identify HHV-6A/B integration sites in clinical samples.

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Epigenetic specifications of host chromosome docking sites for latent Epstein-Barr virus

Cited by 57 publications

References 69 publications

3D landscape of Hepatitis B virus interactions with human chromatins

3D landscape of Hepatitis B virus interactions with human chromatins

Structure-based mapping of the TβRI and TβRII receptor binding sites of the parasitic TGF-β mimic, Hp-TGM

Higher-Order Chromatin Structures of Chromosomally Integrated HHV-6A Predict Integration Sites

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