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Chromatin Regulation of Virus Infection Review TRENDS in Microbiology Vol.14 No.3 March 2006 Chromatin regulation of virus infection Paul M. Lieberman The Wistar Institute, Philadelphia, PA 19104, USA Cellular chromatin forms a dynamic structure that the position of the nucleosome on the DNA and its ability maintains the stability and accessibility of the host to form condensed higher-ordered structures such as DNA genome. Viruses that enter and persist in the heterochromatin can have profound effects on the acces- nucleus must, therefore, contend with the forces that sibility and activity of the packaged DNA. The ATP- drive chromatin formation and regulate chromatin dependent chromatin-remodeling complexes that contain structure. In some cases, cellular chromatin inhibits BRG1, BRM1 or SNF2h can alter the nucleosome viral gene expression and replication by suppressing positions and alter DNA accessibility to promote or DNA accessibility. In other cases, cellular chromatin repress transcription and replication [4]. Histone chaper- provides essential structure and organization to the viral ones and histone variants can also regulate chromosome genome and is necessary for successful completion of functions. For example, histone variant H2AX is phos- the viral life cycle. Consequently, viruses have acquired phorylated in response to DNA double-strand breaks and numerous mechanisms to manipulate cellular chroma- is thought to be essential for the recruitment of DNA tin to ensure viral genome survival and propagation. repair proteins [5]. The signaling mechanism and patterns of recognition, referred to as the histone code hypothesis, A chromatin perspective of virology can be markers for cellular division cycle and cancer Viruses are mobile genetic elements that must navigate prognosis [2,3,6]. It remains to be determined whether a through multiple host-cellular compartments to complete distinct histone modification code or nucleosome organi- their life cycle. The complex and dynamic properties of zation pattern marks viral genomes, infected cellular nuclear chromatin present a formidable challenge to viral genomes or stages of viral infections. gene expression and genome propagation. Recently, a wealth of information has been uncovered regarding the Chromatin organization of viral genomes structure, function and regulation of chromatin during The assembly and organization of nucleosomes on viral complex cellular processes such as differentiation, recom- genomesisthoughttobelinked to the replication bination, ageing and carcinogenesis. Recent studies have mechanism and life cycle of the virus. Persistent DNA also revealed that chromatin has a major role in the life viruses that replicate using cellular replication enzymes cycle of many viruses, and that viruses have coevolved tend to have a chromatin structure that is similar to that with numerous strategies for modulating chromatin- of cellular chromosomes. Acute infections that use viral- related processes. Here, several examples of chromatin specific replication machinery tend to have heterogeneous regulation of virus infection and viral mechanisms of nucleosome composition and modifications associated chromatin modulation are reviewed. with the replicating or parental genomes. Viruses that The bulk of eukaryotic nuclear DNA associates with integrate their genomes, such as HIV, can use different histone-like proteins to form nucleosomal structures, strategies of chromatin manipulation during integration which form the basic unit of cellular chromatin. The and reactivation. RNA viruses, which do not form nucleosome consists of w145 bp of DNA wrapped twice nucleosome structures, can also associate with chromatin around an octamer of the core histones H3, H4, H2A and during replication and transcription of their genomes. In H2B [1]. The histone tails that project out from the core this section, some examples of chromatin organization on can be post-translationally modified by lysine acetylation, several viral genomes are reviewed and the means by lysine and arginine methylation, serine and threonine which chromatin can regulate viral gene expression, DNA phosphorylation and lysine ubiquitylation or sumoylation. replication and integration is considered. Histone tail modifications provide a coding mechanism for protein recognition and signaling at specific locations Acute and persistent DNA viruses within chromatin [2,3]. For example, acetylation of The genomes of many DNA viruses persist for consider- histones H3 and H4 promotes transcription activity by able lengths of time in the host-cell nucleus. The small providing binding sites for bromo domains that are DNA tumor viruses such as simian virus 40 (SV40) and found in several chromatin-modifying and transcription- polyoma virus are assembled into nucleosomal mini- coactivator complexes. Similarly, methylation of histone chromosomes during the DNA replication process. H3 on Lys9 (H3mK9) can recruit the chromo domain of Because these viruses use cellular replication enzymes, heterochromatin protein 1 (HP1) to induce transcription it is thought that these viral minichromosomes are repression. In addition to histone-tail modifications, assembled through a mechanism that is indistinguishable Corresponding author: Lieberman, P.M. ([email protected]). from nucleosome assembly on replicating cellular chromo- Available online 2 February 2006 somes [7]. SV40 and polyoma viruses associate with core www.sciencedirect.com 0966-842X/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tim.2006.01.001 Review TRENDS in Microbiology Vol.14 No.3 March 2006 133 histones during virion encapsidation but lose their (IE) genes. A mutant virus lacking the VP16 activation association with other chromatin proteins, including domain failed to stimulate histone H3 acetylation at lytic linker histones and the chromatin-associated high mobi- cycle promoters [13]. This mutant virus also failed to recruit lity group proteins [8]. histone acetyltransferases CBP and p300, nucleosome Adenoviruses encode their own DNA polymerase and remodeling factors BRG1 and BRM and general transcrip- adenoviral core proteins catalyze the genome condensation tion factors TFIID and RNA polymerase II to IE promoters. that is required for encapsidation so there seems to be no These studies demonstrate that VP16 recruits the cellular opportunity for cellular nucleosome assembly during apparatus that is required to modify and remodel nucleo- adenoviral DNA replication [9]. Nevertheless, adenovirus somes that otherwise inhibit transcription of the parental does not escape chromatin assembly during nuclear entry genomes during the early stages of lytic infection (Figure 1). and the early stages of DNA replication. By six hours post In contrast to acute infection, the latent HSV DNA infection, w50% of the adenovirus DNA is associated with forms structures that are more typical of cellular nucleosomes [10,11]. Nucleosome assembly might be chromatin [14]. During latency, transcription is silenced required for the proper temporal control of viral gene at most viral genes, with the exception of the latency transcription and for the stability of the parent genome associated transcript (LAT). It is thought that chromatin during persistent infections but nucleosomes must be structure has a substantial role in separating the active removed before encapsidation of newly replicated genomes. and inactive regions of transcription within the latent Similar to adenovirus, herpesvirus genomes are genome. The histone-tail modification patterns during assembled into nucleosomal structures during the early latent infection are consistent with this hypothesis stages of lytic infection but lack nucleosomes when [15,16]. The regions that surround the LAT promoter are encapsidated in the virion [12]. During the acute phase enriched in histone H3 acetyl Lys9 and Lys14 relative to of herpes simplex virus (HSV) infection, HSV genomes do the majority of nontranscribed genes of the HSV genome. 0 not form the extended nucleosome arrays typical of bulk The region downstream of the LAT promoter, within the 5 cellular chromatin. However, histones do associate with exon, is also enriched in histone H3 acetylation. The LAT 0 regulatory regions upstream of HSV genes during the 5 exon functions as an enhancer of latent transcription early stages of infection. The histones positioned and is crucial for induced reactivation. This suggests 0 upstream of active genes have post-translational modifi- that the 5 exon might regulate viral gene expression by cations that are characteristic of actively transcribed maintaining a permissive chromatin environment for cellular genes, including enrichment of histone H3 Lys14 latent transcription (Figure 1). acetylation and Lys4 methylation (H3mK4) and the absence of histone H3 Lys9 methylation at promoter Latent episomal viruses start sites [12]. These modification patterns are thought to Hepatitis B virus (HBV), the papillomaviruses and form a code or signal that is permissive for transcription. herpesviruses can form long-term latent infections as Formation of permissive chromatin structure and non-integrated, nucleosome-associated genomes. These histone modifications is an active process induced by the viruses are likely to share many interesting chromatin- HSV encoded virion protein 16 (VP16). VP16 functions as based functions, including the ability to maintain their a potent transcription activator of viral immediate early genomes during cellular division and nuclear breakdown. Lytic HATs HCF SETs
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