An Epigenetic Journey: Epstein-Barr Virus Transcribes Chromatinized and Subsequently Unchromatinized Templates during Its Lytic Cycle

Abstract

The Epstein-Barr virus (EBV) lytic phase, like those of all herpesviruses, proceeds via an orderly cascade that integrates DNA replication and gene expression. EBV early genes are expressed independently of viral DNA amplification, and several early gene products facilitate DNA amplification. On the other hand, EBV late genes are defined by their dependence on viral DNA replication for expression. Recently, a set of orthologous genes found in beta- and gammaherpesviruses have been determined to encode a viral preinitiation complex (vPIC) that mediates late gene expression. The EBV vPIC requires an origin of lytic replication in cis, implying that the vPIC mediates transcription from newly replicated DNA. In agreement with this implication, EBV late gene mRNAs localize to replication factories. Notably, these factories exclude canonical histones. In this review, we compare and contrast the mechanisms and epigenetics of EBV early and late gene expression. We summarize recent findings, propose a model explaining the dependence of EBV late gene expression on lytic DNA amplification, and suggest some directions for future study.

Keywords: DNA methylation; Epstein-Barr virus; chromatin; epigenetics; herpesviruses; histones; transcription.

FIG 1

Early genes (in blue) are expressed independently of viral lytic DNA replication and have more-complex promoter architecture than late genes (red), which are expressed in a DNA replication-dependent manner. Leaky-late genes (purple) can be expressed by both DNA replication-dependent and DNA replication-independent mechanisms, likely because their promoters contain elements from both early and late promoters.

FIG 2

When the EBV lytic cycle is induced, late genes are expressed from a late promoter only when OriLyt is present in cis (10). (A) Both VCAp18 and GFP-VCAp18 are expressed when OriLyt is present on both the full-length EBV genome and the transfected plasmids. (B and C) Only the version of VCAp18 that is present on DNA that has OriLyt in cis is expressed. (D) In the absence of OriLyt, neither version of VCAp18 is expressed.

FIG 3

A model for EBV late gene expression. (A) Early during the lytic cycle, EBV genomes are unreplicated and still chromatinized. The immediate early proteins BZLF1 and BRLF1 can bind to the promoters of early genes (which are usually methylated) and, along with cellular TATA box-binding protein (TBP), recruit RNA polymerase II to transcribe early genes. (B) Later in the lytic phase, EBV genomes are amplified in replication factories, while cellular chromatin moves to the periphery of the nucleus. The amplified viral DNA is unmethylated and unchromatinized, which allows the viral preinitiation complex (vPIC), including the viral TBP BcRF1, to recruit RNA Pol II to late promoters and transcribe late genes.