Chromatin Structure of Epstein–Barr Virus Latent Episomes

Lieberman, Paul M.

doi:10.1007/978-3-319-22822-8_5

Cited by 33 publications

(28 citation statements)

References 212 publications

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“…Chromatin structure and epigenetic modifications contribute significantly to the regulation of EBV latency 5,7 . In the majority of EBV latent infections, the viral genome persists in the nucleus as a chromatinized, covalently closed, circular genome that closely tracks with the host chromosome during cell division cycle.…”

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

et al. 2020

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Epstein-Barr virus (EBV) genomes persist in latently infected cells as extrachromosomal episomes that attach to host chromosomes through the tethering functions of EBNA1, a viral encoded sequence-specific DNA binding protein. Here we employ circular chromosome conformation capture (4C) analysis to identify genome-wide associations between EBV episomes and host chromosomes. We find that EBV episomes in Burkitt's lymphoma cells preferentially associate with cellular genomic sites containing EBNA1 binding sites enriched with B-cell factors EBF1 and RBP-jK, the repressive histone mark H3K9me3, and AT-rich flanking sequence. These attachment sites correspond to transcriptionally silenced genes with GO enrichment for neuronal function and protein kinase A pathways. Depletion of EBNA1 leads to a transcriptional de-repression of silenced genes and reduction in H3K9me3. EBV attachment sites in lymphoblastoid cells with different latency type show different correlations, suggesting that host chromosome attachment sites are functionally linked to latency type gene expression programs.

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

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“…Previous studies have indicated that episome maintenance is mechanistically linked to the establishment of chromatin structures and epigenetic modifications that stabilize viral chromosome transmission during mitosis and viral gene expression during latency [43]. Failure to establish stable epigenetic repression leads to the aberrant expression of lytic cycle genes and lytic DNA replication.…”

Section: Discussionmentioning

confidence: 99%

Carcinoma-risk variant of EBNA1 deregulates Epstein-Barr Virus episomal latency

et al. 2017

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Epstein-Barr Virus (EBV) latent infection is a causative co-factor for endemic Nasopharyngeal Carcinoma (NPC). NPC-associated variants have been identified in EBV-encoded nuclear antigen EBNA1. Here, we solve the X-ray crystal structure of an NPC-derived EBNA1 DNA binding domain (DBD) and show that variant amino acids are found on the surface away from the DNA binding interface. We show that NPC-derived EBNA1 is compromised for DNA replication and episome maintenance functions. Recombinant virus containing the NPC EBNA1 DBD are impaired in their ability to immortalize primary B-lymphocytes and suppress lytic transcription during early stages of B-cell infection. We identify Survivin as a host protein deficiently bound by the NPC variant of EBNA1 and show that Survivin depletion compromises EBV episome maintenance in multiple cell types. We propose that endemic variants of EBNA1 play a significant role in EBV-driven carcinogenesis by altering key regulatory interactions that destabilize latent infection.

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“…While we note that latency III transcripts are induced in Burkitt cell EBV lytic reactivation (27), we speculate that CAF1 depletion may perturb maintenance of EBV genomic DNA methylation through effects on crosstalk between histone and DNA methylation pathways. ChIP-seq approaches demonstrated H3K9me3 and H3K27me3 repressive marks at key lytic and latency gene sites (61, 80, 81). Furthermore, we recently found domains of the enzyme UHRF1 that read H3K9me2/me3, the H3 N-terminus and hemi-methylated DNA are essential for EBV latency I (73).…”

Section: Discussionmentioning

confidence: 99%

Histone loaders CAF1 and HIRA restrict Epstein-Barr virus B-cell lytic reactivation

Zhang

Jiang

Trudeau

et al. 2020

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19Epstein-Barr virus (EBV) infects 95% of adults worldwide and causes infectious mononucleosis. 20 EBV is associated with endemic Burkitt lymphoma, Hodgkin lymphoma, post-transplant 21 lymphomas, nasopharyngeal and gastric carcinomas. In these cancers and in most infected B-cells, 22 Suggestive of an early role in establishment of latency, EBV strongly upregulated CAF1 32 expression in newly infected primary human B-cells prior to the first mitosis, and histone 3.1 and 33 3.3 were loaded on the EBV genome by this timepoint. Knockout of CAF1 subunit CHAF1B 34 impaired establishment of latency in newly EBV-infected Burkitt cells. A non-redundant latency 35 maintenance role was also identified for the DNA synthesis-independent histone 3.3 loader HIRA. 36Since EBV latency also requires histone chaperones ATRX and DAXX, EBV coopts multiple host 37 histone pathways to maintain latency, and these are potential targets for lytic induction therapeutic 38 approaches. 39 40 IMPORTANCE 41Epstein-Barr virus (EBV) was discovered as the first human tumor virus in endemic Burkitt 42 lymphoma, the most common childhood cancer in sub-Saharan Africa. In Burkitt lymphoma and 43 in 200,000 EBV-associated cancers per year, epigenetic mechanisms maintain viral latency, where 44 lytic cycle factors are silenced. This property complicated EBV's discovery and facilitates tumor 45 immunoevasion. DNA methylation and chromatin-based mechanisms contribute to lytic gene 46 silencing. Here, we identify histone chaperones CAF1 and HIRA, which have key roles in host 47 DNA replication-dependent and replication independent pathways, respectively, are each 48 important for EBV latency. EBV strongly upregulates CAF1 in newly infected B-cells, where viral 49 genomes acquire histone 3.1 and 3.3 variants prior to the first mitosis. Since histone chaperones 50 ATRX and DAXX also function in maintenance of EBV latency, our results suggest that EBV 51 coopts multiple histone pathways to reprogram viral genomes and highlights targets for lytic 52 induction therapeutic strategies. 53 54The gamma-herpesvirus Epstein-Barr virus (EBV) persistently infects nearly 95% of adults 59 worldwide (1). EBV is the etiological agent of infectious mononucleosis and is also causally-60 associated with multiple human cancers, including endemic Burkitt lymphoma (eBL), Hodgkin 61 lymphoma, post-transplant lymphoproliferative disease, HIV-associated lymphomas, 62 nasopharyngeal carcinoma and gastric carcinoma (2). Tumor cells contain multiple copies of 63 chromatinized, non-integrated, double-stranded DNA EBV genomes, where incompletely defined 64 epigenetic pathways maintain a state of viral latency and in which most cells do not produce 65 infectious virus. 66 EBV initiates lifelong infection by translocating across the tonsillar epithelium to colonize the 67 B-cell compartment (3, 4). Virion deliver unchromatinized, encapsidated, linear EBV genomes to 68 newly infected cells, which traffic to the nucleus. Upon nuclear entry, incoming genomes are 69 circularized by host D...

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Chromatin Structure of Epstein–Barr Virus Latent Episomes

Cited by 33 publications

References 212 publications

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

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

Carcinoma-risk variant of EBNA1 deregulates Epstein-Barr Virus episomal latency

Histone loaders CAF1 and HIRA restrict Epstein-Barr virus B-cell lytic reactivation

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