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BBA - Gene Regulatory Mechanisms (v.1799, #3-4)
Chromatin tethering and retroviral integration: Recent discoveries and parallels with DNA viruses by Anne M. Meehan; Eric M. Poeschla (pp. 182-191).
Permanent integration of the viral genome into a host chromosome is an essential step in the life cycles of lentiviruses and other retroviruses. By archiving the viral genetic information in the genome of the host target cell and its progeny, integrated proviruses prevent curative therapy of HIV-1 and make the development of antiretroviral drug resistance irreversible. Although the integration reaction is known to be catalyzed by the viral integrase (IN), the manner in which retroviruses engage and attach to the chromatin target is only now becoming clear. Lens epithelium-derived growth factor (LEDGF/p75) is a ubiquitously expressed nuclear protein that binds to lentiviral IN protein dimers at its carboxyl terminus and to host chromatin at its amino terminus. LEDGF/p75 thus tethers ectopically expressed IN to chromatin. It also protects IN from proteosomal degradation and can stimulate IN catalysis in vitro. HIV-1 infection is inhibited at the integration step in LEDGF/p75-deficient cells, and the characteristic lentiviral preference for integration into active genes is also reduced. A model in which LEDGF/p75 acts to tether the viral preintegration complex to chromatin has emerged. Intriguingly, similar chromatin tethering mechanisms have been described for other retroelements and for large DNA viruses. Here we review the evidence supporting the LEDGF/p75 tethering model and consider parallels with these other viruses.
Keywords: Chromatin; Lentivirus; HIV-1; LEDGF/p75; Tether; Herpesvirus; KSHV
Papillomavirus interaction with cellular chromatin by Jianxin You (pp. 192-199).
High-risk human papillomavirus (HPV) infection is the primary risk factor for cervical cancer. HPVs establish persistent infection by maintaining their genomes as extrachromosomal elements (episomes) that replicate along with host DNA in infected cells. The productive life cycle of HPV is intimately tied to the differentiation program of host squamous epithelium. This review examines the involvement of host chromatin in multiple aspects of the papillomavirus life cycle and the malignant progression of infected host cells. Papillomavirus utilizes host mitotic chromosomes as vehicles for transmitting its genetic materials across the cell cycle. By hitchhiking on host mitotic chromosomes, the virus ensures accurate segregation of the replicated viral episomes to the daughter cells during host cell division. This strategy allows persistent maintenance of the viral episome in the infected cells. In the meantime, the virus subverts the host chromatin-remodeling factors to promote viral transcription and efficient propagation of viral genomes. By associating with the host chromatin, papillomavirus redirects the normal cellular control of chromatin to create a cellular environment conducive to both its own survival and malignant progression of host cells. Comprehensive understanding of HPV–host chromatin interaction will offer new insights into the HPV life cycle as well as chromatin regulation. This virus–host interaction will also provide a paradigm for investigating other episomal DNA tumor viruses that share a similar mechanism for interacting with host chromatin.
Keywords: Papillomavirus; Transcription; Cellular chromatin; Episome maintenance
Association of the herpes simplex virus major tegument structural protein VP22 with chromatin by Kristin Ingvarsdottir; John A. Blaho (pp. 200-206).
The abundant tegument protein VP22 has homologs throughout the alphaherpesvirus family. Numerous groups have been involved in the examination of these homologs, trying to decipher their multiple functions. Investigations early on indicated that VP22 associates with chromatin and further evidence has accumulated in recent years, correlating this protein with chromatin and its components. Ongoing and future studies will determine whether this association with chromatin is specific and whether it serves a function during infection in a physiologically relevant setting.
Keywords: Herpes simplex virus; VP22; U; L; 49; Chromatin
Chromosomal tethering and proviral integration by Olivier Delelis; Alessia Zamborlini; Sylvain Thierry; Saib Ali Saïb (pp. 207-216).
Since integration into the host cell genome is an obligatory step for their replication, retro-elements are both potent insertional mutagens and also suitable vectors for gene therapy. Many recent studies reported that the integration process is not random but, on the contrary, higly regulated at the molecular level. Many viral proteins and cellular factors play a key role in the integration step, explaining the reason why different retro-elements display distinct integration profiles. This review describes the recent highlights about integration of retro-elements with particular focus on the mechanisms underlying the specificity of integration target-site selection and the step of chromosomal tethering which preceeds insertion of the provirus.
Keywords: Abbreviations; HIV-1; Human Immunodeficiency Virus type-1; PFV; Primate Foamy Virus; IN; Integrase; NLS; Nuclear Localization Sequence; RT; Reverse Transcriptase; LTR; Long Terminal Repeat; RTC; Reverse Transcription Complex; PIC; Pre-integration Complex; LEDGF; Lens Epithelial-Derived Growth FactorRetrotransposon; Lentiviruses; Viral integration; HIV-1; Integrase; Pre-integration; Complex
Chromatin assembly on herpes simplex virus genomes during lytic infection by Xu Lu; Steven J. Triezenberg (pp. 217-222).
The human herpes simplex viruses HSV-1 and HSV-2 infect a significant portion of the human population. Both viruses can undergo lytic infection in epithelial cells and establish lifelong latency in neuronal cells. The large HSV-1 DNA genomes have long been considered to be devoid of histones both inside the virion particle and inside the cell during lytic infection, but to be packaged in repressive chromatin during latency. However, recent reports indicate that many histone and non-histone chromosomal proteins can associate with viral DNA during lytic infection and may influence important events during the HSV-1 lytic cycle. In this article, we summarize recent developments in this field and their implications.
Keywords: Herpes simplex virus; HSV-1; Chromatin-modifying coactivator; Histone acetyltransferase; Chromatin remodeling enzyme; VP16; Histone; Nucleosome; Lytic infection; Latent infection
Chromatin dynamics during herpes simplex virus-1 lytic infection by Brandon J. Placek; Shelley L. Berger (pp. 223-227).
Herpes simplex virus type 1 is a DNA virus that can establish lytic infections in epithelial cells and latent infections in sensory neurons. Upon entry into the nucleus the genome of HSV-1 rapidly associates with histone proteins. Similar to the genomes of the cellular host, HSV-1 is subject to chromatin-based regulation of transcription and replication. However, unlike the host genome, nucleosomes appear to be underrepresented on the HSV genome. During lytic infection, when the genome is transcribed, the HSV-1 chromatin structure appears to be disorganized, and characterized by histone variant sub-types and post-translational modifications representative of active chromatin. In contrast, during latency, when the majority of the viral genome is transcriptionally silent, the chromatin is compacted into a regularly repeating, compact heterochromatic structure. Here we discuss recent studies that underscore the importance of chromatin regulation during the lytic phase of the HSV-1 life-cycle.
Keywords: HSV-1; Chromatin; Histone variant; Transcription
Epigenetic regulation of latent Epstein–Barr virus promoters by Maria Takacs; Ferenc Banati; Anita Koroknai; Judit Segesdi; Daniel Salamon; Hans Wolf; Hans Helmut Niller; Janos Minarovits (pp. 228-235).
Epigenotypes are modified cellular or viral genotypes that differ in transcriptional activity in spite of having an identical or nearly identical DNA sequence. Restricted expression of latent, episomal Epstein–Barr virus (EBV) genomes is a consequence of a series of epigenetic modifications. In tight latency, there is no virus production (lytic viral replication, associated with the expression of all viral genes), and only a limited set of viral promoters is activated in a host-cell-dependent manner. The latent EBV promoters control the expression of growth-transformation-associated viral genes. The role of major epigenetic mechanisms in the regulation of latent EBV promoters is variable. DNA methylation contributes to silencing of Wp and Cp (alternative promoters for transcripts coding for nuclear antigens EBNA 1-6) and LMP1p, LMP2Ap and LMP2Bp (promoters for transcripts encoding transmembrane proteins). DNA methylation does not control, however, Qp (a promoter for EBNA1 transcripts only) in B lymphoblastoid cell lines (LCLs, immortalized by EBV in vitro), although in vitro methylated Qp-reporter gene constructs are silenced. The invariably unmethylated Qp is probably switched off by binding of a repressor protein in LCLs.Histone modifications may also contribute to the regulation of latent EBV promoters because the active Cp, Qp and LMP2Ap promoters that are marked by strong binding of cellular regulatory proteins are located on “acetylation islands” enriched in diacetylated histone H3 and tetraacetylated histone H4. We speculate that binding of the chromatin insulator protein CTCF to 3 distinct sites (within, close to and far from the matrix attachment region) may contribute to the three-dimensional organization of the viral episomes. We also raise the point that latent EBV episomes may relocate to new nuclear subcompartments before the start of lytic EBV replication. We propose that a similar relocation of EBV episomes may result in a promoter switch (from Qp to Cp) due to the access of Cp to a B-lymphoblast-specific transcription factory when in vitro cultivated Burkitt's lymphoma cells undergo a phenotypic drift.
Keywords: Epstein-Barr virus; DNA methylation; histone modifications; locus control region; CTCF; matrix attachment region; transcription factory
Chromatin organization of gammaherpesvirus latent genomes by Italo Tempera; Paul M. Lieberman (pp. 236-245).
The gammaherpesviruses are a subclass of the herpesvirus family that establish stable latent infections in proliferating lymphoid and epithelial cells. The latent genomes are maintained as multicopy chromatinized episomes that replicate in synchrony with the cellular genome. Importantly, most of the episomes do not integrate into the host chromosome. Therefore, it is essential that the viral “minichromosome” establish a chromatin structure that is suitable for gene expression, DNA replication, and chromosome segregation. Evidence suggests that chromatin organization is important for each of these functions and plays a regulatory role in the establishment and maintenance of latent infection. Here, we review recent studies on the chromatin organization of the human gammaherpesviruses, Epstein–Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). We discuss the potential role of viral origins of DNA replication and viral encoded origin-binding proteins like EBNA1 and LANA in establishment of viral chromosome organization during latent infection. We also discuss the roles of host cell factors, like CTCF and cohesins, that contribute to higher-order chromosome structures that may be important for stable gene expression programs during latent infection in proliferating cells.
Keywords: EBV; KSHV; CTCF; Cohesin; ORC; Histone
Epigenetic regulation of latent HSV-1 gene expression by David C. Bloom; Nicole V. Giordani; Dacia L. Kwiatkowski (pp. 246-256).
Like other alpha-herpesviruses, Herpes Simplex Virus Type 1 (HSV-1) possesses the ability to establish latency in sensory ganglia as a non-integrated, nucleosome-associated episome in the host cell nucleus. Transcription of the genome is limited to the Latency-Associated Transcript (LAT), while the lytic genes are maintained in a transcriptionally repressed state. This partitioning of the genome into areas of active and inactive transcription suggests epigenetic control of HSV-1 latent gene expression. During latency viral transcription is not regulated by DNA methylation but likely by post-translational histone modifications. The LAT region is the only region of the genome enriched in marks indicative of transcriptional permissiveness, specifically dimethyl H3 K4 and acetyl H3 K9, K14, while the lytic genes appear under-enriched in those same marks. In addition, facultative heterochromatin marks, specifically trimethyl H3 K27 and the histone variant macroH2A, are enriched on lytic genes during latency. The distinct epigenetic domains of the LAT and the lytic genes appear to be separated by chromatin insulators. Binding of CTCF, a protein that binds to all known vertebrate insulators, to sites within the HSV-1 genome likely prevents heterochromatic spreading and blocks enhancer activity. When the latent viral genome undergoes stress-induced reactivation, it is possible that CTCF binding and insulator function are abrogated, enabling lytic gene transcription to ensue. In this review we summarize our current understanding of latent HSV-1 epigenetic regulation as it pertains to infections in both the rabbit and mouse models. CTCF insulator function and regulation of histone tail modifications will be discussed. We will also present a current model of how the latent genome is carefully controlled at the epigenetic level and how stress-induced changes to it may trigger reactivation.
Keywords: Herpes; HSV; Chromatin; CTCF; Insulator; Latency; Epigenetic; Polycomb
Control of α-herpesvirus IE gene expression by HCF-1 coupled chromatin modification activities by Thomas M. Kristie; Yu Liang; Jodi L. Vogel (pp. 257-265).
The immediate early genes of the α-herpesviruses HSV and VZV are transcriptionally regulated by viral and cellular factors in a complex combinatorial manner. Despite this complexity and the apparent redundancy of activators, the expression of the viral IE genes is critically dependent upon the cellular transcriptional coactivator HCF-1. Although the role of HCF-1 had remained elusive, recent studies have demonstrated that the protein is a component of multiple chromatin modification complexes including the Set1/MLL1 histone H3K4 methyltransferases. Studies using model viral promoter–reporter systems as well as analyses of components recruited to the viral genome during the initiation of infection have elucidated the significance of HCF-1 chromatin modification complexes in contributing to the final state of modified histones assembled on the viral IE promoters. Strikingly, the absence of HCF-1 results in the accumulation of nucleosomes bearing repressive marks on the viral IE promoters and silencing of viral gene expression.
Keywords: Abbreviations; HCF-1; Host Cell Factor-1; HSV; herpes simplex virus; VZV; varicella zoster virus; HMT; histone methyltransferase; HDM; histone demethylase; MLL1; mixed-lineage leukemia; LSD1; lysine-specific demethylase 1; H3K4; histone H3-lysine 4; H3K9; histone H3-lysine 9HCF-1; Herpesvirus; Coactivator; Set1; LSD1
The HTLV-1 Tax protein: Revealing mechanisms of transcriptional activation through histone acetylation and nucleosome disassembly by Jennifer K. Nyborg; Dinaida Egan; Neelam Sharma (pp. 266-274).
The human T-cell leukemia virus, type-1 (HTLV-1)-encoded Tax protein is required for high-level transcription of the virus. Tax function is strictly dependent upon the phosphorylated form of the cellular transcription factor CREB (pCREB), and together they bind novel cAMP response elements located within the viral promoter. The DNA-bound Tax/pCREB complex recruits the cellular coactivators CBP/p300, which are essential for viral gene expression. The coactivators, via their histone acetyltransferase activity, function to promote changes in chromatin architecture that are permissive to transcriptional activation. Tax expression in vivo recruits p300 to the HTLV-1 promoter and correlates with depletion of nucleosomes from the integrated provirus. We recently developed a novel in vitro, chromatin-based experimental system that recapitulates the eviction of nucleosomes from the HTLV-1 promoter observed in vivo. These assays establish the essential function of Tax/pCREB recruitment of CBP/p300, and concomitant histone acetylation, in the nucleosome disassembly process. These observations are of particular significance, as Tax mediates disassembly of the full nucleosome octamer independent of transcriptional activity and ATP utilization. Instead, nucleosome eviction is absolutely dependent upon acetyl CoA and the histone chaperone Nap1. In this review, we will discuss HTLV-1, Tax transactivation, and our recent findings that uncover the critical role of Tax in promoting chromatin transitions that accompany activation of viral transcription. We will describe the phenomenon of acetylation-dependent promoter nucleosome disassembly and the emerging view that the formation of nucleosome-free promoter regions may represent a general prerequisite for transcriptional activation in eukaryotes.
Keywords: HTLV; Tax; Nucleosome eviction; Histone acetylation; Chromatin; CBP; p300; CREB
Chromatin dynamics associated with HIV-1 Tat-activated transcription by Rebecca Easley; Rachel Van Duyne; Will Coley; Irene Guendel; Sherry Dadgar; Kylene Kehn-Hall; Fatah Kashanchi (pp. 275-285).
Chromatin remodeling is an essential event for HIV-1 transcription. Over the last two decades this field of research has come to the forefront, as silencing of the HIV-1 provirus through chromatin modifications has been linked to latency. Here, we focus on chromatin remodeling, especially in relation to the transactivator Tat, and review the most important and newly emerging studies that investigate remodeling mechanisms. We begin by discussing covalent modifications that can alter chromatin structure including acetylation, deacetylation, and methylation, as well as topics addressing the interplay between chromatin remodeling and splicing. Next, we focus on complexes that use the energy of ATP to remove or secure nucleosomes and can additionally act to control HIV-1 transcription. Finally, we cover recent literature on viral microRNAs which have been shown to alter chromatin structure by inducing methylation or even by remodeling nucleosomes.
Keywords: Tat; HIV-1; Chromatin remodeling; RNAi; SWI/SNF; Post-translational modification
Chromatin structure regulates human cytomegalovirus gene expression during latency, reactivation and lytic infection by John Sinclair (pp. 286-295).
Infection of cells with human cytomegalovirus (HCMV) has two potential outcomes. For instance, infection of fibroblasts results in extensive viral gene expression, viral DNA replication and release of progeny virus. In contrast, in undifferentiated myeloid cells, the lytic transcription programme of HCMV is effectively suppressed and cells undergo latent infection.It is now accepted that the suppression of viral lytic gene expression observed during latency in myeloid cells is a result of the inability of undifferentiated cell types to support robust viral immediate early (IE) gene expression — crucial genes responsible for driving the lytic cycle. The repression of IE gene expression in undifferentiated myeloid cells, at least in part, results from specific post-translational modifications of histones associated with the viral major immediate early promoter (MIEP). In cells of the early myeloid lineage, the histone modifications present on the MIEP impart on it a repressive chromatin structure preventing transcriptional activity. Reactivation of HCMV lytic infection is correlated to changes in histone modifications around the MIEP resulting in a chromatin structure conducive to transcriptional activity. These changes are intimately linked with the differentiation of myeloid cells — a phenomenon known to reactivate latent virus in vivo. Chromatin structure of the viral MIEP, therefore, plays a crucial role in latency and reactivation of this persistent human herpesvirus.Whether chromatin-mediated regulation of viral lytic gene expression also occurs, is only beginning to be addressed. However, recent work suggests that all classes of lytic HCMV promoters are subjected to regulation by post-translational modification of their associated histones throughout the time course of infection. Incoming viral genomes appear to be the targets of intrinsic cellular defence mechanisms which attempt to silence viral gene expression through chromatinisation. Viral functions eventually overcome these cellular repression mechanisms permitting high levels of IE gene expression which results in modification of the chromatin structure of early and late gene promoters driving a regulated cascade of viral lytic gene expression and virus production.
Keywords: Cytomegalovirus; Latency; Reactivation; Chromatin; Histone modification; Lytic infection; Transcriptional regulation
Viral-encoded enzymes that target host chromatin functions by Hua Wei; Ming-Ming Zhou (pp. 296-301).
Ever since their existence, there has been an everlasting arms race between viruses and their host cells. Host cells have developed numerous strategies to silence viral gene expression whereas viruses always find their ways to overcome these obstacles. Recent studies show that viruses have also evolved to take full advantage of existing cellular chromatin components to activate or repress its own genes when needed. While in most cases viruses encode certain proteins to recruit or inhibit cellular factors through physical interactions, growing examples show that viral-encoded enzymes affect host chromatin structure through post-translationally modifying histones or other cellular proteins important for chromatin function. The most well-studied example is vSET encoded by paramecium bursaria chlorella virus 1. vSET specifically methylates histone H3 at lysine 27, causing genome-wide silencing of Polycomb target genes upon infection, thus mimicking the function of Polycomb repressive complex 2 (PRC2) in eukaryotes. Other examples include BGLF4 from Epstein–Barr virus that affects both condensin and topoisomerase II activity and Us3 from Herpes Simplex virus 1 that inhibits HDAC1 function through phosphorylation.
Keywords: Epigenetics; Chromatin; Virus; Histone modification; SET domain; Methyltransferase
Diversity and evolution of chromatin proteins encoded by DNA viruses by Robson F. de Souza; Lakshminarayan M. Iyer; L. Aravind (pp. 302-318).
Double-stranded DNA viruses display a great variety of proteins that interact with host chromatin. Using the wealth of available genomic and functional information, we have systematically surveyed chromatin-related proteins encoded by dsDNA viruses. The distribution of viral chromatin-related proteins is primarily influenced by viral genome size and the superkingdom to which the host of the virus belongs. Smaller viruses usually encode multifunctional proteins that mediate several distinct interactions with host chromatin proteins and viral or host DNA. Larger viruses additionally encode several enzymes, which catalyze manipulations of chromosome structure, chromatin remodeling and covalent modifications of proteins and DNA. Among these viruses, it is also common to encounter transcription factors and DNA-packaging proteins such as histones and IHF/HU derived from cellular genomes, which might play a role in constituting virus-specific chromatin states. Through all size ranges a subset of domains in viral chromatin proteins appears to have been derived from those found in host proteins. Examples include the Zn-finger domains of the E6 and E7 proteins of papillomaviruses, SET domain methyltransferases and Jumonji-related demethylases in certain nucleocytoplasmic large DNA viruses and BEN domains in poxviruses and polydnaviruses. In other cases, chromatin-interacting modules, such as the LXCXE motif, appear to have been widely disseminated across distinct viral lineages, resulting in similar retinoblastoma targeting strategies. Viruses, especially those with large linear genomes, have evolved a number of mechanisms to manipulate viral chromosomes in the process of replication-associated recombination. These include topoisomerases, Rad50/SbcC-like ABC ATPases and a novel recombinase system in bacteriophages utilizing RecA and Rad52 homologs. Larger DNA viruses also encode SWI2/SNF2 and A18-like ATPases which appear to play specialized roles in transcription and recombination. Finally, it also appears that certain domains of viral provenance have given rise to key functions in eukaryotic chromatin such as a HEH domain of chromosome tethering proteins and the TET/JBP-like cytosine and thymine hydroxylases.
Keywords: Chromatin; SWI2/SNF2; E6; E7; E1A; PHD; Treble clef; LXCXE; RecA; A18R; Topoisomerase; ATPase; Rad52; HEH; Histone; Methylase; Demethylase; Jumonji
Chromatin at the intersection of viral infection and DNA damage by Caroline E. Lilley; Mira S. Chaurushiya; Matthew D. Weitzman (pp. 319-327).
During infection, viruses cause global disruption to nuclear architecture in their attempt to take over the cell. In turn, the host responds with various defenses, which include chromatin-mediated silencing of the viral genome and activation of DNA damage signaling pathways. Dynamic exchanges at chromatin, and specific post-translational modifications on histones have recently emerged as master controllers of DNA damage signaling and repair. Studying viral control of chromatin modifications is identifying histones as important players in the battle between host and virus for control of cell cycle and gene expression. These studies are revealing new complexities of the virus–host interaction, uncovering the potential of chromatin as an anti-viral defense mechanism, and also providing unique insights into the role of chromatin in DNA repair.
Keywords: Virus; Chromatin; DNA repair; Histone H2AX
The transcriptional code of human IFN-β gene expression by Ethan Ford; Dimitris Thanos (pp. 328-336).
Activation of interferon-β transcription is a highly ordered process beginning with the delivery of NF-κB to the IFN-β enhancer through a process involving stochastic interchromosomal interactions between the IFN-β enhancer and specialized Alu elements. NF-κB delivery is followed by the binding of ATF-2/c-Jun and IRF proteins in a highly cooperative fashion. The assembled “enhanceosome” then recruits PCAF/GCN5 which acetylates the histone tails of the adjacent nucleosomes. The transcriptional coactivator CBP, which binds in a complex with the RNA polymerase II holoenzyme is recruited by the enhanceosome replacing PCAF/GCN5. Next, SWI/SNF, which is part of the holoenzyme complex, induces a conformational change in a nucleosome positioned over the transcriptional start site allowing TFIID to bind, which promotes the sliding of this nucleosome to a new downstream position. At this point the full pre-initiation complex is assembled and transcription commences. This detailed picture of the IFN-β transcription program gathered through years of rigorous studies, now serves as a paradigm for understanding complex transcriptional switches in eukaryotic systems.
Keywords: Chromatin; Transcription; Enhanceosome; Interferon-β; NF-κB; IRF-3
RNA silencing directed against geminiviruses: Post-transcriptional and epigenetic components by Priya Raja; Jamie N. Wolf; David M. Bisaro (pp. 337-351).
It is well-established that plants use cytoplasmic, post-transcriptional gene silencing (PTGS) as a defense against RNA viruses and DNA virus transcripts. More recently, it has become clear that small RNA-directed methylation leading to transcriptional gene silencing (TGS) is also used as a defense against DNA virus chromatin. Here we use the DNA-containing geminiviruses as models to discuss what is currently known about both types of antiviral silencing, and viral suppression of PTGS and TGS as a counterdefense.
Keywords: Viral chromatin; Methylation; Silencing suppression; AL2 protein; L2 protein