Cohesins Repress Kaposi's Sarcoma-Associated Herpesvirus Immediate Early Gene Transcription during Latency

Chen, Horng-Shen; Wikramasinghe, Priyankara; Showe, Louise C.; Lieberman, Paul M.

doi:10.1128/jvi.00787-12

Cited by 72 publications

(124 citation statements)

References 86 publications

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“…These data suggest that modulation of the chromatin in the Rta promoter is a critical mechanism for regulating the KSHV latent/lytic switch. During latency, Rta's 3.0-kb promoter is decorated with histones that bear modifications associated with both repression of transcription (histone H3 trimethylated at lysine 27 [H3K27-me3] and H3K9-me3) and activation of transcription (acetylation of histone H3 [H3K9/K14-ac] and H3K4-me3) (19)(20)(21)(22). A similar pattern of bivalent histone modifications is seen on cellular genes that are transcriptionally repressed but are poised to respond to signals that switch on their transcription (23).…”

Section: K Aposi's Sarcoma (Ks)-associated Herpesvirus (Kshv) Is Thementioning

confidence: 99%

Histone Deacetylase Classes I and II Regulate Kaposi's Sarcoma-Associated Herpesvirus Reactivation

Shin

DeCotiis

Giron

et al. 2014

J Virol

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In primary effusion lymphoma (PEL) cells infected with latent Kaposi's sarcoma-associated herpesvirus (KSHV), the promoter of the viral lytic switch gene, Rta, is organized into bivalent chromatin, similar to cellular developmental switch genes. Histone deacetylase (HDAC) inhibitors (HDACis) reactivate latent KSHV and dramatically remodel the viral genome topology and chromatin architecture. However, reactivation is not uniform across a population of infected cells. We sought to identify an HDACi cocktail that would uniformly reactivate KSHV and reveal the regulatory HDACs. Using HDACis with various specificities, we found that class I HDACis were sufficient to reactivate the virus but differed in potency. Valproic acid (VPA) was the most effective HDACi, inducing lytic cycle gene expression in 75% of cells, while trichostatin A (TSA) induced less widespread lytic gene expression and inhibited VPA-stimulated reactivation. VPA was only slightly superior to TSA in inducing histone acetylation of Rta's promoter, but only VPA induced significant production of infectious virus, suggesting that HDAC regulation after Rta expression has a dramatic effect on reactivation progression. Ectopic HDACs 1, 3, and 6 inhibited TPA-stimulated KSHV reactivation. Surprisingly, ectopic HDACs 1 and 6 stimulated reactivation independently, suggesting that the stoichiometries of HDAC complexes are critical for the switch. Tubacin, a specific inhibitor of the ubiquitin-binding, proautophagic HDAC6, also inhibited VPA-stimulated reactivation. Immunofluorescence indicated that HDAC6 is expressed diffusely throughout latently infected cells, but its expression level and nuclear localization is increased during reactivation. Overall, our data suggest that inhibition of HDAC classes I and IIa and maintenance of HDAC6 (IIb) activity are required for optimal KSHV reactivation.

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Section: K Aposi's Sarcoma (Ks)-associated Herpesvirus (Kshv) Is Thementioning

confidence: 99%

Histone Deacetylase Classes I and II Regulate Kaposi's Sarcoma-Associated Herpesvirus Reactivation

Shin

DeCotiis

Giron

et al. 2014

J Virol

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“…Previous studies have shown that CTCF binding sites in the KSHV latency control region compromise viral episome maintenance (26) and alter latency transcription control, including deregulation of LANA and derepression of lytic transcripts for K14/vGPCR (34,35). Other studies revealed that CTCF and cohesin mediate interactions between the latent and lytic control regions (35) and that the loss of cohesin, but not CTCF, leads to derepression of lytic immediateearly gene transcription (34). Whether the DNA-looping function and chromatin-organizing activity of CTCF are related to histone modifications, RNAPII binding, or RNA processing has not been resolved.…”

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confidence: 99%

“…In addition, CTCF can interact with RNA polymerase II (RNAPII) (31), alter nucleosome positions and histone variant enrichment (32), and influence histone modification patterns (33). Previous studies have shown that CTCF binding sites in the KSHV latency control region compromise viral episome maintenance (26) and alter latency transcription control, including deregulation of LANA and derepression of lytic transcripts for K14/vGPCR (34,35). Other studies revealed that CTCF and cohesin mediate interactions between the latent and lytic control regions (35) and that the loss of cohesin, but not CTCF, leads to derepression of lytic immediateearly gene transcription (34).…”

mentioning

confidence: 99%

CTCF Regulates Kaposi's Sarcoma-Associated Herpesvirus Latency Transcription by Nucleosome Displacement and RNA Polymerase Programming

Kang

Cho

Sung

et al. 2013

J Virol

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d CCCTC-binding factor (CTCF) has been implicated in various aspects of viral and host chromatin organization and transcriptional control. We showed previously that CTCF binds to a cluster of three sites in the first intron of the Kaposi's sarcoma-associated herpesvirus (KSHV) multicistronic latency-associated transcript that encodes latency-associated nuclear antigen (LANA), viral cyclin (vCyclin), vFLIP, viral microRNAs, and kaposin. We show here that these CTCF binding sites regulate mRNA production, RNA polymerase II (RNAPII) programming, and nucleosome organization of the KSHV latency transcript control region. We also show that KSHV bacmids lacking these CTCF binding sites have elevated and altered ratios of spliced latency transcripts. CTCF binding site mutations altered RNAPII and RNAPII-accessory factor interactions with the latency control region. CTCF binding sites were required for the in vitro recruitment of RNAPII to the latency control region, suggesting that direct interactions between CTCF and RNAPII contribute to transcription regulation. Histone modifications in the latency control region were also altered by mutations in the CTCF binding sites. Finally, we show that CTCF binding alters the regular phasing of nucleosomes in the latency gene transcript and intron, suggesting that nucleosome positioning can be an underlying biochemical mechanism of CTCF function. We propose that RNAPII interactions and nucleosome displacement serve as a biochemical basis for programming RNAPII in the KSHV transcriptional control region. K aposi's sarcoma-associated herpesvirus (KSHV), also referred to as human herpesvirus 8 (HHV8), is a human gammaherpesvirus that infects ϳ15% of the world's population and can establish long-term latent infection in B lymphocytes of infected individuals (1-3). The virus was identified originally as the etiological agent associated with all forms of Kaposi's sarcoma (KS) (4) and was subsequently shown to be associated with pleural effusion lymphoma (PEL) and multicentric Castleman's disease (4-6; reviewed in references 2, 3, and 7). Viral pathogenesis and persistence depend on a complex balance between latent and lytic infection. In most latently infected cells, viral gene transcription is limited to a region of the viral chromosome that encodes latencyassociated nuclear antigen (LANA/ORF73), viral cyclin (vCyclin/ ORF72), vFLIP (ORF71), viral microRNAs (vmiRNAs), and kaposin (K12) (8, 9), which are critical for viral genome maintenance and host cell survival during latent infection (2, 7, 10). The latency transcripts have complex structures, with multicistronic messages and several alternative promoters, as well as lytic gene promoters for both sense and antisense orientations. Proper regulation of these various transcripts is essential for viral persistence and host cell survival.Transcriptional regulation and mRNA processing of the KSHV major latency transcripts have been investigated in some detail (8,9,(11)(12)(13)(14)(15)(16). Transcription initiation has been mapped to a s...

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“…Whilst not yet demonstrated in alphaherpesviruses, stress-induced dissociation of CTCF/cohesin leading to release of paused RNA polymerase II in early stages of latent Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) reactivation has been documented (Kang & Lieberman, 2011;Chen et al, 2012). Overall, epigenetic regulation of latent HSV-1 gene transcription is an exquisite mechanism through which virus can undergo rapid animation in response to cellular stress, resulting in transcription of multiple genes independent of de novo protein synthesis.…”

Section: Alphaherpesvirus Gene Transcription Is Deregulated During VImentioning

confidence: 99%

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

Kennedy

Rovnak

Badani

et al. 2015

Journal of General Virology

137

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Herpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses that cause lifelong infections in ganglia. Following primary infection and establishment of latency, HSV-1 reactivation typically results in herpes labialis (cold sores), but can occur frequently elsewhere on the body at the site of primary infection (e.g. whitlow), particularly at the genitals. Rarely, HSV-1 reactivation can cause encephalitis; however, a third of the cases of HSV-1 encephalitis are associated with HSV-1 primary infection. Primary VZV infection causes varicella (chickenpox) following which latent virus may reactivate decades later to produce herpes zoster (shingles), as well as an increasingly recognized number of subacute, acute and chronic neurological conditions. Following primary infection, both viruses establish a latent infection in neuronal cells in human peripheral ganglia. However, the detailed mechanisms of viral latency and reactivation have yet to be unravelled. In both cases latent viral DNA exists in an 'end-less' state where the ends of the virus genome are joined to form structures consistent with unit length episomes and concatemers, from which viral gene transcription is restricted. In latently infected ganglia, the most abundantly detected HSV-1 RNAs are the spliced products originating from the primary latency associated transcript (LAT). This primary LAT is an 8.3 kb unstable transcript from which two stable (1.5 and 2.0 kb) introns are spliced. Transcripts mapping to 12 VZV genes have been detected in human ganglia removed at autopsy; however, it is difficult to ascribe these as transcripts present during latent infection as early-stage virus reactivation may have transpired in the post-mortem time period in the ganglia. Nonetheless, low-level transcription of VZV ORF63 has been repeatedly detected in multiple ganglia removed as close to death as possible. There is increasing evidence that HSV-1 and VZV latency is epigenetically regulated. In vitro models that permit pathway analysis and identification of both epigenetic modulations and global transcriptional mechanisms of HSV-1 and VZV latency hold much promise for our future understanding in this complex area. This review summarizes the molecular biology of HSV-1 and VZV latency and reactivation, and also presents future directions for study. Received 5 January 2015Accepted 18 March 2015 IntroductionHerpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses usually acquired early in life. Primary HSV-1 infection is usually localized and may be asymptomatic, although it can produce a more widespread systemic infection in neonates and immunocompromised adults, whilst primary VZV infection is systemic and results in childhood varicella (chickenpox). During primary infection, both viruses gain access to neurons most likely through retrograde transport from the site of cutaneous lesion...

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Cohesins Repress Kaposi's Sarcoma-Associated Herpesvirus Immediate Early Gene Transcription during Latency

Cited by 72 publications

References 86 publications

Histone Deacetylase Classes I and II Regulate Kaposi's Sarcoma-Associated Herpesvirus Reactivation

Histone Deacetylase Classes I and II Regulate Kaposi's Sarcoma-Associated Herpesvirus Reactivation

CTCF Regulates Kaposi's Sarcoma-Associated Herpesvirus Latency Transcription by Nucleosome Displacement and RNA Polymerase Programming

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

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