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Review
. 2015 Jan 14;7(1):112-42.
doi: 10.3390/cancers7010112.

Chromatinization of the KSHV Genome During the KSHV Life Cycle

Timsy Uppal  1 , Hem C Jha  2 , Subhash C Verma  3 , Erle S Robertson  4
Affiliations
Review

Chromatinization of the KSHV Genome During the KSHV Life Cycle

Timsy Uppal et al. Cancers (Basel). .

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) belongs to the gamma herpesvirus family and is the causative agent of various lymphoproliferative diseases in humans. KSHV, like other herpesviruses, establishes life-long latent infection with the expression of a limited number of viral genes. Expression of these genes is tightly regulated by both the viral and cellular factors. Recent advancements in identifying the expression profiles of viral transcripts, using tilling arrays and next generation sequencing have identified additional coding and non-coding transcripts in the KSHV genome. Determining the functions of these transcripts will provide a better understanding of the mechanisms utilized by KSHV in altering cellular pathways involved in promoting cell growth and tumorigenesis. Replication of the viral genome is critical in maintaining the existing copies of the viral episomes during both latent and lytic phases of the viral life cycle. The replication of the viral episome is facilitated by viral components responsible for recruiting chromatin modifying enzymes and replication factors for altering the chromatin complexity and replication initiation functions, respectively. Importantly, chromatin modification of the viral genome plays a crucial role in determining whether the viral genome will persist as latent episome or undergo lytic reactivation. Additionally, chromatinization of the incoming virion DNA, which lacks chromatin structure, in the target cells during primary infection, helps in establishing latent infection. Here, we discuss the recent advancements on our understating of KSHV genome chromatinization and the consequences of chromatin modifications on viral life cycle.

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Figures

Figure 1
Figure 1
The chromatinization and maintenance of the KSHV genome following de novo infection: After the KSHV virion attaches to the host cell, the viral capsid enters the cytoplasm, followed by the ejection of viral DNA into the nucleus. Subsequently, the linear viral genome is circularized into an extrachromosomal episome to avoid detection by the host DNA damage response; (2) Circularized genome is further chromatinized using cellular histones and histone modifying factors resulting in a stable episome; (3) Viral genome, which is being maintained as multicopy chromatinized episome then replicates along with the cellular genome; (4) For the stable persistence and segregation of KSHV epigenome during latency, KSHV latent protein LANA binds to the TR region of the viral genome and tethers the viral genome to the host chromosome through its amino-terminus via interaction with histones and cellular chromatin associated proteins.
Figure 2
Figure 2
The chromatin landscape of the KSHV genome during various phases of viral life cycle. Following primary infection, promoters of the key latent genes get epigenetically modified with activating histone marks (H3K4me3/acH3) resulting in the expression of those genes throughout the viral life cycle. In contrast, KSHV lytic gene promoters possess either H3K27Ac/H3K4Me3-rich, active chromatin or H3Ac/H3K4Me3/H3K27Me3-rich bivalent chromatin. During latency, the lytic gene promoters are epigenetically modified with H3K9Me3/H3K27Me3 marks to form a heterochromatin. However, upon reactivation these repressive histone marks are enzymatically removed and gets modified with the activating histone marks (H3K4Me3/H3Ac).
Figure 3
Figure 3
Polycomb repressive complexes (PRC1 and PRC2) and Polyadenylated RNA-mediated control of KSHV RTA promoter during latency and lytic reactivation. (A) During latency, the histone methyltransferase EZH2 subunit of PRC2 and RING 1A/B subunit of PRC1 bind to the KSHV genome and colocalizes with corresponding repressive histone marks H3K27me3 and H2AK119ub, respectively, leading to silencing of the target genes; (B) Lytic reactivation, triggered by the dissociation of PRC2 and PRC1 from the viral genome or inhibition of EZH2 by chemical compounds, leads to the enrichment of activating histone marks on the viral genome and the activation of gene transcription. PAN RNA, which is highly expressed during lytic reactivation, recruits several cellular and viral chromatin factors (MLL2, JMJD3 and UTX) to the RTA promoter and triggers the expression of immediate early, RTA protein.
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