Abstract
Establishment of viral latency is not only essential for lifelong Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, but it is also a prerequisite of viral tumorigenesis. The latent viral DNA has a complex chromatin structure, which is established in a stepwise manner regulated by host epigenetic factors during de novo infection. However, despite the importance of viral latency in KSHV pathogenesis, we still have limited information about the repertoire of epigenetic factors that are critical for the establishment and maintenance of KSHV latency. Therefore, the goal of this study was to identify host epigenetic factors that suppress lytic KSHV genes during primary viral infection, which would indicate their role in latency establishment. We performed an siRNA screen targeting 392 host epigenetic factors during primary infection and analyzed which ones affect the expression of the viral replication and transcription activator (RTA) and/or the latency-associated nuclear antigen (LANA), which are viral genes essential for lytic replication and latency, respectively. As a result, we identified the Nucleosome Remodeling and Deacetylase (NuRD) complex, Tip60 and Tip60-associated co-repressors, and the histone demethylase KDM2B as repressors of KSHV lytic genes during both de novo infection and the maintenance of viral latency. Furthermore, we showed that KDM2B rapidly binds to the incoming viral DNA as early as 8 hpi, and can limit the enrichment of activating histone marks on the RTA promoter favoring the downregulation of RTA expression even prior to the polycomb proteins-regulated heterochromatin establishment on the viral genome. Strikingly, KDM2B can also suppress viral gene expression and replication during lytic infection of primary gingival epithelial cells, revealing that KDM2B can act as a host restriction factor of the lytic cycle of KSHV during both latent and lytic infections in multiple different cell types.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic virus that causes lifelong infection in humans by alternating between latency and a lytic cycle in various cell types [1]
The epigenetic factors that we identified as suppressors of KSHV lytic genes are crucial for the establishment and maintenance of KSHV latency in different cell types, and several of them can block lytic KSHV infection in oral epithelial cells
Since herpesviruses often rely on similar sets of host epigenetic factors, the characterization of these newly identified epigenetic factors in KSHV infection may help to better understand fundamental epigenetic mechanisms that may be utilized by other herpesviruses to establish latency following primary infection
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic virus that causes lifelong infection in humans by alternating between latency and a lytic cycle in various cell types [1]. The KSHV DNA is maintained as a chromatinized episome in the nuclei of infected cells, which is regulated by host epigenetic factors. Several antagonistic epigenetic factors have been reported to be capable of binding to and regulating the activity of the RTA promoter. These include specific histone methyltransferases and demethylases as well as histone acetyltransferases and deacetylases, which can determine whether KSHV remains in latency or undergoes lytic reactivation in latently infected cells [6,10,20,21,22]
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