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Review
. 2013 Dec;11(12):863-75.
doi: 10.1038/nrmicro3135. Epub 2013 Nov 6.

Keeping it quiet: chromatin control of gammaherpesvirus latency

Paul M Lieberman  1
Affiliations
Review

Keeping it quiet: chromatin control of gammaherpesvirus latency

Paul M Lieberman. Nat Rev Microbiol. 2013 Dec.

Abstract

The human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) establish long-term latent infections associated with diverse human cancers. Viral oncogenesis depends on the ability of the latent viral genome to persist in host nuclei as episomes that express a restricted yet dynamic pattern of viral genes. Multiple epigenetic events control viral episome generation and maintenance. This Review highlights some of the recent findings on the role of chromatin assembly, histone and DNA modifications, and higher-order chromosome structures that enable gammaherpesviruses to establish stable latent infections that mediate viral pathogenesis.

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Figures

Figure 1
Figure 1. Early events that regulate the establishment of a latent gammaherpesvirus minichromosome
Depiction of the early events affecting the fate of gammaherpesvirus genomes. Receptor-mediated signaling sets the stage for viral gene expression programmes. Entry of the viral DNA into the nucleus activates IFI16, leading to inflammasome activation (in the case of KSHV) and may trigger the DNA damage response (DDR) following recognition by ATM kinase. The linear genome then undergoes circularization and chromatinization, which results in the formation of a stable episome. The viral tegument proteins ORF75 (for KSHV) and BNRF1 (for EBV) have a key role in promoting chromatinization, by disrupting proteins in PML-NBs, for example Daxx and ATRX.
Fig. 2
Fig. 2. Establishment of the EBV epigenome
(A) EBV primary infection initiates with transcription from the latent W promoter (Wp) and the lytic Zta promoter. Lower levels of Qp and LMP1 transcripts are also detected. PAX5 and host immediate early factors have an important role in early transcription programming of viral gene expression. (B) Type III latency is established when EBNA2 expression is sufficient to stabilize Cp and LMP1 and LMP2 promoter initiation. EBNA2 binds RBP-jK at Cp and PU.1 at LMP1 promoter. Silencing of the Zta promoter is mediated by repressors, like ZEB. Loop formation is detected between OriP and Cp, and OriP and LMP1/LMP2 region. (C) Type I latency occurs when Cp is silenced by DNA methylation. OriP forms an exclusive loop with Qp, but not Cp
Fig. 3
Fig. 3. Establishment of the KSHV epigenome
(A) Primary infection of KSHV results in combination of both lytic and latent transcription. (B) Latency is stabilized by a CTCFI-cohesin loop between immediate early promoter region (ORF50–ORF45–46–47) and latency control region (LANA-vCyc-vFLIP). RBP-jK functions as a scaffold for activation by Rta (encoded by ORF50) during lytic and for repression by LANA during latency.
Fig. 4
Fig. 4. Episome Maintenance and Viral Chromosome Structure
(A) Both EBNA1 and LANA tether the viral episomes to metaphase chromosomes. (Top) The tethering domains of EBNA1 are RGG-like and capable of binding to G-quadruplex RNA and ORC, EBP2, and AT-rich DNA. (Bottom) The N-terminal tethering domain of LANA interacts with histones H2A/H2B. LANA can also interact with other candidate chromatin mediators, including DEK, RBP-jK, and BRD2/4 proteins capable of binding acetylated lysines in the H3 or H4 N-terminal tails. (B) Both EBV and KSHV form sister chromatid catenations that depend on replication fork stalling or terminaton at the episome maintenance elements. EBV OriP and KSHV TR function as a replication fork blocks that recruit Timeless-Tipin replication fork protection complex and promote sister-chromatid linkages (catenations). Timeless and Tipin are essential for episome maintenance, and may be required for the establishment of stable epigenomes.
Fig. 5
Fig. 5. Chromosome Control of Lytic Reactivation
(A) Factors that restrict lytic replication of KSHV include the histone H3K27 trimethylase EZH2 and polycomb repression complex that prevents the transcription of the ORF50/Rta immediate early gene. Additional controls include the CTCF-cohesin binding sites upstream and downstream of the ORF50 IE promoter control region, and the cohesin linkage between IE and lytic control regions. (B) EBV lytic control is provided by host-cell factors that repress the BZLF1/Zta IE control region, including ZEB, Jun dimer binding protein (Jun DBP), and CTCF. A cohesin loop between the Zta IE region and the LMP1/2 control region may repress lytic, similar to that observed in KSHV. Additional restrictions to lytic activation include the repressive interaction of Zta with Oct2, and the requirement for methylated DNA at Zta responsive promoters. Stat1/2 and EBF1 have also been implicated in restricting lytic cycle reactivation.
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