Abstract
Kaposi’s sarcoma-associated herpesvirus is an oncogenic γ-herpesvirus that causes latent infection in humans. In cells, the viral genome adopts a highly organized chromatin structure, which is controlled by a wide variety of cellular and viral chromatin regulatory factors. In the past few years, interrogation of the chromatinized KSHV genome by whole genome-analyzing tools revealed that the complex chromatin landscape spanning the viral genome in infected cells has important regulatory roles during the viral life cycle. This review summarizes the most recent findings regarding the role of histone modifications, histone modifying enzymes, DNA methylation, microRNAs, non-coding RNAs and the nuclear organization of the KSHV epigenome in the regulation of latent and lytic viral gene expression programs as well as their connection to KSHV-associated pathogenesis.
Highlights
It is estimated that 15% of human cancers are caused by viral infections
The fact that lytic reactivation of KSHV can be induced by treating latently infected cells with chemicals that affect chromatin regulatory factors such as histone deacetylases (HDACs), DNA methyltransferases (DNMTs) and histone acetyltransferases (HATs) argues that chromatin and chromatin-associated factors must be involved in the control of viral gene expression [11,12,13]
In contrast to the immediate early (IE)/E gene-rich genomic regions of KSHV, the parts of the viral genome that encode many of the late genes are mainly associated with the repressive H3K9me3 and H3K27me3 and these chromatin marks are presumably responsible for the inhibition of late gene expression during latency and during the early phase of reactivation
Summary
It is estimated that 15% of human cancers are caused by viral infections. Among the seven currently known human oncogenic viruses, two of them belong to the herpesvirus family: Kaposi’s sarcoma-associated herpesvirus (KSHV or Human Herpesvirus 8, HHV-8) and Epstein-Barr virus (EBV or Human Herpesvirus 4, HHV-4). The fact that lytic reactivation of KSHV can be induced by treating latently infected cells with chemicals that affect chromatin regulatory factors such as histone deacetylases (HDACs), DNA methyltransferases (DNMTs) and histone acetyltransferases (HATs) argues that chromatin and chromatin-associated factors must be involved in the control of viral gene expression [11,12,13]. Depending on whether a gene is destined for activation or silencing, different histone modifying enzyme complexes are recruited to the gene promoter to generate specific posttranslational modifications on histones called histone marks, which function as key modulators of gene expression (Figure 1B) [16]. We will highlight some unanswered questions that require further investigation to better understand the fundamental chromatin-regulatory pathways involved in the control of the different stages of the KSHV lifecycle
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