The Epstein-Barr Virus Episome Maneuvers between Nuclear Chromatin Compartments during Reactivation.

Stephanie A Moquin,Samantha G Fernandez,Sean Whalen,Alix Warburton,Sean Thomas,Katherine S Pollard,Alison A Mcbride,Jj L Miranda,Jae U Jung

doi:10.1128/jvi.01413-17

Abstract

ABSTRACTThe 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 on the EBV side localize 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 on the human side localize to gene-poor and AT-rich 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 myriad interchromosomal associations also suggests a role for this type of long-range association in gene regulation.IMPORTANCE The 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 mechanisms similar to those of the human genome to regulate transcription. We found that the EBV genome associates with repressive compartments of the nucleus during latency and with active compartments during reactivation. This study advances our knowledge of the EBV life cycle, adding three-dimensional relocalization as a novel component to the molecular events that occur during reactivation. Furthermore, the data add to our understanding of nuclear compartments, showing that disperse interchromosomal interactions may be important for regulating transcription.

Highlights

Since the EBV genome has a structure similar to that of human chromatin and uses similar mechanisms to control transcription at the protein level, we wondered whether the virus uses the 3D structure and functional organization of the nucleus to regulate gene expression and the genetic switch to a very transcriptionally active state
We used in situ high-throughput chromosome conformation capture (Hi-C) [2] to measure interactions between the EBV genome and the human genome during latency and reactivation
We show here that during latency, the EBV genome uses a small genetic element to interact with a network of repressive heterochromatin

Summary

Introduction

Since the EBV genome has a structure similar to that of human chromatin and uses similar mechanisms to control transcription at the protein level, we wondered whether the virus uses the 3D structure and functional organization of the nucleus to regulate gene expression and the genetic switch to a very transcriptionally active state. We used in situ high-throughput chromosome conformation capture (Hi-C) [2] to measure interactions between the EBV genome and the human genome during latency and reactivation. We show here that during latency, the EBV genome uses a small genetic element to interact with a network of repressive heterochromatin. The viral genome engages in different associations to leave this repressive environment and surround itself with active euchromatin

Methods

Results

Conclusion