Control of cytomegalovirus lytic gene expression by histone acetylation

Murphy, Jane; Fischle, Wolfgang; Verdin, Eric; Sinclair, John

doi:10.1093/emboj/21.5.1112

Cited by 204 publications

(288 citation statements)

References 76 publications

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“…Although HCMV virion contains no histone proteins [55,56], a number of reports indicate that host histones with different modifications associate with HCMV DNA in infected cells cultured in labs or isolated from humans [49,[57][58][59][60][61][62]. Nitzsche et al [43] further indicate that HCMV DNA is chromatinized in infected cells; histones are localized with UL44 at replication foci and there is a robust increase of histone occupancy coupled with viral DNA replication.…”

Section: Discussionmentioning

confidence: 99%

Host-viral effects of chromatin assembly factor 1 interaction with HCMV IE2

Lee

et al. 2011

Cell Res

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Chromatin assembly factor 1 (CAF1) consisting of p150, p60 and p48 is known to assemble histones onto newly synthesized DNA and thus maintain the chromatin structure. Here, we show that CAF1 expression was induced in human cytomegalovirus (HCMV)-infected cells, concomitantly with global chromatin decondensation. This apparent conflict was thought to result, in part, from CAF1 mislocalization to compartments of HCMV DNA synthesis through binding of its largest subunit p150 to viral immediate-early protein 2 (IE2). p150 interaction with p60 and IE2 facilitated HCMV DNA synthesis. The IE2Q548R mutation, previously reported to result in impaired HCMV growth with unknown mechanism, disrupted IE2/p150 and IE2/histones association in our study. Moreover, IE2 interaction with histones partly depends on p150, and the HCMV-induced chromatin decondensation was reduced in cells ectopically expressing the p150 mutant defective in IE2 binding. These results not only indicate that CAF1 was hijacked by IE2 to facilitate the replication of the HCMV genome, suggesting chromatin assembly plays an important role in herpesviral DNA synthesis, but also provide a model of the virus-induced chromatin instability through CAF1.

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Section: Discussionmentioning

confidence: 99%

Host-viral effects of chromatin assembly factor 1 interaction with HCMV IE2

Lee

et al. 2011

Cell Res

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Section: Discussionmentioning

confidence: 99%

“…Observations which show that YY1 can not only block the recruitment of the general transcription factor TFIIB to a pre-initiation complex on the MIEP, but can also recruit the chromatin re-modelling factor histone deacetylase 3 (HDAC3), offer at least two possible mechanisms for the specific repression of MIEP activity by this factor (Sinclair, 1999;Thomas & Seto, 1999). Indeed, we have recently shown that chromatin acetylation/deacetylation plays a major role in the control of the NIEP in permissive and non-permissive cells (Murphy et al, 2002).Our results reiterate that there is a degree of redundancy with respect to the sites through which a number of candidate repressors can prevent expression from the MIEP. Thus YY1 and ERF interact not only with the dyad repeat element, but also with the repeated 21 bp motif (Liu et al, 1994; Figs 2 and 4).…”

mentioning

confidence: 99%

Ets-2 Repressor Factor (ERF) mediates repression of the human cytomegalovirus major immediate-early promoter in undifferentiated non-permissive cells

Bain

Mendelson

Sinclair

2003

Journal of General Virology

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The repression of human cytomegalovirus immediate-early (IE) lytic gene expression is crucial for the maintenance of the latent viral state. By using conditionally permissive cell lines, which provide a good model for the differentiation state-dependent repression of IE gene expression, we have identified several cellular factors that bind to the major immediate-early promoter (MIEP) and whose expression is down-regulated after differentiation to a permissive phenotype. Here we show that the cellular protein Ets-2 Repressor Factor (ERF) physically interacts with the MIEP and represses MIEP activity in undifferentiated non-permissive T2 embryonal carcinoma cells. This factor binds to the dyad element and the 21 bp repeats within the MIEP -regions known to be important for the negative regulation of MIEP activity. Finally, we show that following differentiation to a permissive phenotype ERF's repressive effects are severely abrogated. INTRODUCTIONHuman cytomegalovirus (HCMV) is a betaherpesvirus whose sero-prevalence can vary from 50 to 90 % depending on the socio-economic status of the population. Following primary infection, which rarely causes disease in the immunocompetent, HCMV maintains a latent infection throughout the lifetime of the infected host. However, infection or reactivation in the immunocompromised, such as transplant recipients or AIDS patients, is associated with morbidity and mortality (reviewed in Alford & Britt, 1993).Productive HCMV infection and reactivation require an ordered cascade of gene expression and are dependent on the expression of the immediate-early (IE) gene products IE72 and IE86 (also known as IE1 and IE2 respectively). These IE proteins are potent and promiscuous transactivators of both cellular and viral genes, and serve to activate the viral early (E) gene promoters (Pizzorno et al., 1988;Malone et al., 1990), ultimately leading to viral DNA replication, expression of the viral late (L) genes and virus assembly. The expression of IE72 and IE86 is under the control of the major immediate-early promoter (MIEP), a highly complex region comprising a TATA box, an upstream imperfect dyad symmetry element (also termed the modulator), and an extremely powerful enhancer region made up of a series of 17, 18, 19 and 21 bp repeat motifs (reviewed in Meier & Stinski, 1996). MIEP activity is regulated by a myriad of positively and negatively acting cellular and viral proteins. For example, there are numerous nuclear factor-1 (NF-1) sites within the MIEP and the 18 and 19 bp repeat sequences contain NF-kB and cyclic AMPresponsive element binding protein (CREB) binding sites respectively (Meier & Stinski, 1996). Conversely, several studies using non-permissive cells have shown that the modulator and the 21 bp repeats are responsible for the inhibition of MIEP activity in such cells (Nelson et al., 1987;Lubon et al., 1989;Kothari et al., 1991).In vivo, monocytes have been identified as an important site of HCMV latency (Taylor-Wiedeman et al., 1991); these cells carry the viral genome in t...

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“…93 Consequently, this might be used as an approach to render cytomegalovirus latently infected cells transiently visible to the host immune response ( Figure 6). In initial pilot experiments, we have been able to induce IE gene expression using histone deacetylase inhibitors in latently infected monocytes (Poole et al, unpubl.…”

Section: Induction Of Immunogenic Lytic Genes In the Absence Of Immunmentioning

confidence: 99%

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

et al. 2014

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While the host immune response following primary human cytomegalovirus (HCMV) infection is generally effective at stopping virus replication and dissemination, virus is never cleared by the host and like all herpesviruses, persists for life. At least in part, this persistence is known to be facilitated by the ability of HCMV to establish latency in myeloid cells in which infection is essentially silent with, importantly, a total lack of new virus production. However, although the viral transcription programme during latency is much suppressed, a number of viral genes are expressed during latent infection at the protein level and many of these have been shown to have profound effects on the latent cell and its environment. Intriguingly, many of these latency-associated genes are also expressed during lytic infection. Therefore, why the same potent host immune responses generated during lytic infection to these viral gene products are not recognized during latency, thereby allowing clearance of latently infected cells, is far from clear. Reactivation from latency is also a major cause of HCMV-mediated disease, particularly in the immune compromised and immune naive, and is also likely to be a major source of virus in chronic subclinical HCMV infection which has been suggested to be associated with long-term diseases such as atherosclerosis and some neoplasias. Consequently, understanding latency and why latently infected cells appear to be immunoprivileged is crucial for an understanding of the pathogenesis of HCMV and may help to design strategies to eliminate latent virus reservoirs, at least in certain clinical settings.

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Control of cytomegalovirus lytic gene expression by histone acetylation

Cited by 204 publications

References 76 publications

Host-viral effects of chromatin assembly factor 1 interaction with HCMV IE2

Host-viral effects of chromatin assembly factor 1 interaction with HCMV IE2

Ets-2 Repressor Factor (ERF) mediates repression of the human cytomegalovirus major immediate-early promoter in undifferentiated non-permissive cells

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

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