The Epstein-Barr virus episome maneuvers between nuclear chromatin compartments during reactivation

Abstract

The human genome is structurally organized in three---dimensional space to facilitate functional partitioning of transcription. We learned that the latent episome of the human Epstein---Barr virus (EBV) preferentially associates with gene---poor chromosomes and avoids gene---rich chromosomes. Kaposi's sarcoma---associated herpesvirus behaves similarly, but human papillomavirus does not. Contacts localize on the EBV side to OriP, the latent origin of replication. This genetic element, and the EBNA1 protein that binds there, are sufficient to reconstitute chromosome association preferences of the entire episome. Contacts localize on the human side to gene---poor regions of chromatin distant from transcription start sites. Upon reactivation from latency, however, the episome moves away from repressive heterochromatin and toward active euchromatin. Our work adds three---dimensional relocalization to the molecular events that occur during reactivation. Involvement of a myriad of interchromosomal associations also suggests a role for this type of long---range association in gene regulation. IMPORTANCEThe human genome is structurally organized in three---dimensional space, and this structure functionally affects transcriptional activity. We set out to investigate whether a double stranded DNA virus, Epstein---Barr virus (EBV), uses similar mechanisms as the human genome to regulate transcription. We found that the EBV genome associates with repressive compartments of the nucleus during latency and active compartments during reactivation. This study is advances our knowledge of the EBV life cycle, adding three---dimensional re---localization as a novel component to the molecular events that occur during reactivation. Furthermore, the data adds to our understanding of nuclear compartments, showing that disperse interchromosomal interactions may be important for regulating transcription.

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

“…1a and Supplementary Table 2, 3). We identified numerous EBV 4C peaks throughout chromosomes with 10 kb resolution indicating that EBV tethering sites can be identified at the gene level and at higher resolution than previous studies 48 . The overall pattern of EBV 4C peaks from 5 baits revealed common peaks at specific genomic regions and a general distribution of peaks throughout all chromosomes.…”

“…A recent study using Hi-C methods examined EBV interactions with host chromosome in various cell types 48 . In this study, EBV was found to associate with gene poor, AT-rich locations restricted to a subset of chromosomes through an EBNA1 independent, but OriP-dependent mechanism 48 . There are several technical differences in this Hi-C study compared to ours.…”

Parvovirus minute virus of mice interacts with sites of cellular DNA damage to establish and amplify its lytic infection

“…The EBV interactome has also been characterized using in-situ Hi-C assays, which generate chromosome conformation maps that provide a snapshot of how every restriction enzyme site associates with every other site throughout the genome. These studies showed that the latent EBV episome associates with gene poor regions, but relocalizes to gene-rich regions of the genome upon reactivation ( Moquin et al, 2017 ). While highly informative, these studies did not have the resolving power of the assays described here for MVM.…”

Oncogenic Properties of the EBV ZEBRA Protein

“…For example, BMRF1 induces centrosome amplification and chromosome instability in B cells in vitro and in vivo in a mouse model [ 118 ]. BGLF4 directly or indirectly induces DNA damage by retarding cellular S-phase progression or inducing premature chromosome condensation associated with a high risk of chromosomal breaks at common fragile sites [ 119 , 120 , 121 ]. EBV DNase was also found to induce GI in human epithelial cells through DNA damage induction and DNA repair repression [ 122 ].…”