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• W3041760426 abstract "Viral genomes encode transcriptional regulators that alter the expression of viral and host genes. Despite an emerging role in human diseases, a thorough annotation of human viral transcriptional regulators (vTRs) is currently lacking, limiting our understanding of their molecular features and functions. Here, we provide a comprehensive catalog of 419 vTRs belonging to 20 different virus families. Using this catalog, we characterize shared and unique cellular genes, proteins, and pathways targeted by particular vTRs and discuss the role of vTRs in human disease pathogenesis. Our study provides a unique and valuable resource for the fields of virology, genomics, and human disease genetics. Viral genomes encode transcriptional regulators that alter the expression of viral and host genes. Despite an emerging role in human diseases, a thorough annotation of human viral transcriptional regulators (vTRs) is currently lacking, limiting our understanding of their molecular features and functions. Here, we provide a comprehensive catalog of 419 vTRs belonging to 20 different virus families. Using this catalog, we characterize shared and unique cellular genes, proteins, and pathways targeted by particular vTRs and discuss the role of vTRs in human disease pathogenesis. Our study provides a unique and valuable resource for the fields of virology, genomics, and human disease genetics. Over 200 viral species infect humans (Knipe and Howley, 2013Knipe D.M. Howley P.M. Fields Virology.Sixth Edition. Wolters Kluwer/Lippincott Williams & Wilkins Health, 2013Google Scholar). During the course of an infection, the human body can host up to hundreds of trillions of viruses. When viruses infect human cells, a wide variety of cytopathic effects are induced and counteracted by the host innate and adaptive defense systems, often resulting in illness. Viruses can also affect human health through changes to cellular processes that contribute to non-infectious human diseases. Indeed, the role of viruses in promoting cancer has been well-studied, and viruses also have been implicated in dozens of other chronic human diseases. New viral pathogenic threats continue to emerge, such as SARS-CoV-2. Understanding the functional roles played by viral proteins is therefore of critical importance for combatting these ongoing threats to human health. The genomes of DNA and RNA viruses encode multiple proteins required to control gene expression, genome replication, and transmission to other host cells. Among these proteins, viral transcription factors (TFs), cofactors, and other regulators of gene expression are central to human disease pathogenesis due to their ability to control the expression of both viral and host genes. Herein, we use the term “vTR” to refer to any virus-encoded protein capable of modulating gene transcription through direct or indirect interactions with nucleic acids. vTRs can be broadly split into two basic categories—“primary” vTRs are proteins whose primary function is the regulation of specific gene targets. “Secondary” vTRs are proteins that have other functions, such as DNA replication or nucleic acid transport that can also “moonlight” as transcriptional regulators. vTRs have been identified in multiple virus families, in both DNA and RNA viruses. These proteins, together with host transcriptional regulators, coordinate viral and human gene expression at multiple levels, including chromatin organization, RNA polymerase II (RNA Pol II) recruitment, transcription initiation, and transcription elongation (Figure 1). Although multiple vTRs have been shown to play central roles in human biological and disease processes, there is no single resource providing a comprehensive review of vTRs, limiting our understanding of their shared and unique molecular features, functional roles, evolutionary conservation, and roles in human diseases. This lack of an in-depth census likely stems from challenges in identifying and characterizing these proteins. In contrast to eukaryotic TFs, vTRs can rarely be classified into families based on conserved DNA-binding domains (DBDs) (e.g., homeodomains, nuclear hormone receptors, etc.). In addition, given that most vTRs did not arise from duplication events, sequence homology can usually only identify orthologous vTRs from related viruses, and only rarely reveals large classes of structurally related vTRs. Finally, many viral genomes evolve at high rates, rendering sequence-based homology searches largely ineffectual. Thus, vTR identification to date has usually relied on individual studies characterizing the function of a single vTR using experimental methods such as DNA-binding assays, chromatin immunoprecipitation, and perturbation studies followed by measurement of target gene expression. Further, these studies have been performed for only a subset of vTRs using different experimental approaches and analyses criteria, making it challenging to perform integrative data analyses. The field of virology has contributed substantially to our understanding of fundamental biological processes, including reverse transcription, the structure and function of gene promoters, RNA splicing, polyadenylation, and the domain-like nature of proteins (Enquist, 2009Enquist L.W. Editors of the Journal of VirologyVirology in the 21st century.J. Virol. 2009; 83: 5296-5308Crossref PubMed Scopus (31) Google Scholar). Many researchers have dedicated their lives to understanding the molecular features, evolutionary conservation, and functions of vTRs. The purpose of this review is not to offer a historical perspective on these important contributions. Instead, our goal is to build upon this body of work by synthesizing the currently available information, and use the resulting new resource to obtain a “30,000 foot” perspective. We are also optimistic that the availability of this resource will offer new opportunities as the relatively nascent field of viral functional genomics continues to move forward. Here, we describe an extensive and systematic census of the vTRs encoded by human DNA and RNA viruses. Our approach combines thorough literature searches with functional classifications and systematic homology analyses to create the first compendium of human vTRs. In total, we identified 419 vTRs across 20 virus families. Using this resource and available datasets, we address several outstanding questions: What is the distribution of vTRs across virus families? What cellular pathways do vTRs affect? How conserved are vTRs at the protein level? What are the roles of particular vTRs in disease? Collectively, our compendium and analyses provide a solid foundation for future vTR studies. vTRs are classically identified through experiments demonstrating their impact on gene expression and in vitro and in vivo assays that establish nucleic acid binding. For example, vTRs that directly interact with DNA have been identified through in vitro binding experiments such as electrophoretic mobility shift assays (EMSAs), protein pull-downs, and DNase footprinting assays. Such assays can both demonstrate the ability of a vTR to bind to DNA and determine a subset of the recognized DNA sequences. To date, exhaustive examination of in vitro vTR DNA-binding specificities to establish DNA-binding motifs has only been performed for a single vTR (of the 171 DNA-binding vTRs in our catalog)—the Epstein-Barr virus (EBV)-encoded Zta protein (Tillo et al., 2017Tillo D. Ray S. Syed K.S. Gaylor M.R. He X. Wang J. Assad N. Durell S.R. Porollo A. Weirauch M.T. Vinson C. The Epstein-Barr Virus B-ZIP Protein Zta Recognizes Specific DNA Sequences Containing 5-Methylcytosine and 5-Hydroxymethylcytosine.Biochemistry. 2017; 56: 6200-6210Crossref PubMed Scopus (13) Google Scholar). In contrast, roughly 75% of the ~1,600 human TFs currently have established DNA-binding motifs (Lambert et al., 2019Lambert S.A. Yang A.W.H. Sasse A. Cowley G. Albu M. Caddick M.X. Morris Q.D. Weirauch M.T. Hughes T.R. Similarity regression predicts evolution of transcription factor sequence specificity.Nat. Genet. 2019; 51: 981-989Crossref PubMed Scopus (53) Google Scholar). There are likely several reasons for the limited number of available vTR motifs. First, given that vTRs have been traditionally studied in the context of regulation of viral genes, most studies have focused on the few regions of the viral genomes bound by the vTRs rather than fully characterizing their DNA-binding specificities. Second, methods that exhaustively determine binding specificities, such as protein binding microarrays, systematic evolution of ligands by exponential enrichment (SELEX), and bacterial one-hybrid assays, generally have a higher success rate when testing DBDs rather than full-length proteins (Berger and Bulyk, 2009Berger M.F. Bulyk M.L. Universal protein-binding microarrays for the comprehensive characterization of the DNA-binding specificities of transcription factors.Nat. Protoc. 2009; 4: 393-411Crossref PubMed Scopus (260) Google Scholar; Jolma et al., 2013Jolma A. Yan J. Whitington T. Toivonen J. Nitta K.R. Rastas P. Morgunova E. Enge M. Taipale M. Wei G. et al.DNA-binding specificities of human transcription factors.Cell. 2013; 152: 327-339Abstract Full Text Full Text PDF PubMed Scopus (800) Google Scholar; Meng et al., 2005Meng X. Brodsky M.H. Wolfe S.A. A bacterial one-hybrid system for determining the DNA-binding specificity of transcription factors.Nat. Biotechnol. 2005; 23: 988-994Crossref PubMed Scopus (156) Google Scholar). However, DBDs have not been determined for most DNA-binding vTRs. Finally, many vTRs only bind DNA in complex with host TFs. Although binding assays can be performed for heterodimers (Jolma et al., 2015Jolma A. Yin Y. Nitta K.R. Dave K. Popov A. Taipale M. Enge M. Kivioja T. Morgunova E. Taipale J. DNA-dependent formation of transcription factor pairs alters their binding specificity.Nature. 2015; 527: 384-388Crossref PubMed Scopus (308) Google Scholar; Siggers et al., 2011Siggers T. Chang A.B. Teixeira A. Wong D. Williams K.J. Ahmed B. Ragoussis J. Udalova I.A. Smale S.T. Bulyk M.L. Principles of dimer-specific gene regulation revealed by a comprehensive characterization of NF-κB family DNA binding.Nat. Immunol. 2011; 13: 95-102Crossref PubMed Scopus (147) Google Scholar), these experiments are challenging to perform. Heterodimers and protein complexes are thus more frequently studied using EMSA or chromatin immunoprecipitation (ChIP); neither assay can fully characterize DNA-binding specificities. Although in vitro assays can establish the ability of vTRs to bind to specific DNA sequences, they are not always perfectly reflective of in vivo DNA binding specificities. Further, in vitro assays do not reveal the timing or functional consequences of these genomic binding events. Several studies have therefore employed ChIP in virus-infected cells or cells transfected with a particular vTR. ChIP followed by high-throughput sequencing (ChIP-seq) is increasingly used to study vTR binding to the host genome, with 55 datasets currently available for 16 different vTRs (Table S1). In addition, functional studies (e.g., reporter and overexpression assays) have been used to identify host and viral gene targets of vTRs and determine their activation or repression activities. Many vTRs do not directly bind to nucleic acids, instead exerting their function through interactions with host regulators. These vTRs have been identified and characterized through protein-protein binding assays (e.g., yeast two-hybrid or immunoprecipitation followed by mass spectrometry), based on interactions with host TFs and cofactors (Gordon et al., 2020Gordon D.E. Jang G.M. Bouhaddou M. Xu J. Obernier K. White K.M. O’Meara M.J. Rezelj V.V. Guo J.Z. Swaney D.L. et al.A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.Nature. 2020; (Published online April 30, 2020)https://doi.org/10.1038/s41586-020-2286-9Crossref PubMed Scopus (2570) Google Scholar; Ronco et al., 1998Ronco L.V. Karpova A.Y. Vidal M. Howley P.M. Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity.Genes Dev. 1998; 12: 2061-2072Crossref PubMed Scopus (512) Google Scholar). In addition, non-nucleic acid binding vTRs have been studied using many of the same methods that are used for nucleic acid binding vTRs, such as EMSA, ChIP, and reporter assays, because these methods are also amenable to protein complexes. Despite a central role for vTRs in viral and human biology, a thorough census of vTRs has not been previously undertaken. We therefore employed a hybrid “curation and computation” approach (Figure S1) to create a comprehensive list of 419 vTRs encoded in the genomes of viruses that infect humans (Table S2). Paralogous vTRs were identified by within-species and cross-species amino acid homology searches using BLASTp and CD-HIT (Fu et al., 2012Fu L. Niu B. Zhu Z. Wu S. Li W. CD-HIT: accelerated for clustering the next-generation sequencing data.Bioinformatics. 2012; 28: 3150-3152Crossref PubMed Scopus (4650) Google Scholar). Multiple lines of evidence were considered for each candidate vTR, including the data supporting its ability to bind nucleic acids and alter gene expression levels. Data sources, including binding ligands (double-stranded DNA [dsDNA], single-stranded DNA [ssDNA], double-stranded RNA [dsRNA], and/or single-stranded RNA [ssRNA]), biochemical assays (e.g., EMSA, SELEX, reporter assays), crystal structures, and functional annotations are provided on the project website (http://vtr.cchmc.org/vtrsurvey/) and in Table S2. In total, we identified and annotated vTRs from 20 different DNA and RNA virus families. Inspection of the vTR catalog reveals that the genomes of human viruses can encode as many as 16 vTRs (the herpesviruses EBV and Kaposi’s sarcoma-associated virus [KSHV]) (Figure 2A). The Poxviridae and Herpesviridae families, which have the largest genome sizes, also have the highest number of currently known vTRs per virus, with an average of 13 and 9.6, respectively. Herpesviruses have the widest range of vTRs (6 to 16), while other families encode a more consistent number. This vTR diversity parallels the higher variation in species diversity, genome structure, tropism, and replication cycles observed in herpesviruses. In contrast, the genomes of RNA viruses in our catalog encode an average of only 1.6 vTRs (Figure 2B). This is likely related both to the compact genome of RNA viruses and to differences in replication and gene expression strategies relative to DNA viruses. We next classified vTRs into DNA-binding, RNA-binding, DNA/RNA-binding, or indirect/ unknown binding. Most DNA and RNA virus vTRs either directly bind DNA or RNA, respectively, or are indirect binders that act as cofactors (Figures 2C and 2D). However, while many DNA virus vTRs can directly regulate both viral and host gene expression due to their ability to bind to DNA, RNA virus vTRs usually indirectly regulate the expression of host genes through interactions with host TFs, cofactors, or RNA Pol II, because they largely are incapable of binding DNA (Figures 2C and 2D). Whereas primary vTRs mainly function as controllers of gene expression, secondary vTRs are also involved in other molecular functions such as nucleic acid replication, transport, packaging, and DNA repair (Figure 2E). For example, most virus families encode proteins that play roles in both transcriptional regulation and viral genome replication, such as E2A (adenovirus), UL29 (Herpes simplex virus 1 [HSV-1]), and BMRF1 (EBV). Similarly, many viruses encode proteins involved in both gene regulation and packaging the viral genome, including the nucleoprotein from arenaviruses, VP30 and VP35 from filoviruses, and Rep52 from parvoviruses. Other functions are more specific to secondary vTRs from certain families, such as the involvement of herpesvirus and polyomavirus vTRs in DNA repair. Although both DNA and RNA viruses encode secondary vTRs, secondary vTRs are significantly more prevalent in RNA viruses (Figure 2F), likely due to the compact genome of RNA viruses, which results in gene products with pleiotropic functions. Like other types of viral proteins, vTRs can exhibit high genetic diversity across isolates of a given viral species. For example, the E6 and E7 vTRs of type 5 human papillomavirus (HPV) both attain pairwise protein amino acid identity as low as ~30% across isolates (Table S3). Interestingly, this high sequence variation is not simply a result of general viral genome diversification. To illustrate, the EBV EBNA2 and EBNA3A/B/C proteins, which play key roles in viral latency, show high diversity (48%–77% amino acid identity between certain EBV isolates). In contrast, most other EBV vTRs do not display such high variability, including BALF2, BcRF1, and BDLF4 proteins, which have a sequence identity close to 100%. This can be explained by the strong evolutionary constraint of proteins that function in the context of a highly conserved multiprotein complex such as these (Gruffat et al., 2016Gruffat H. Marchione R. Manet E. Herpesvirus Late Gene Expression: A Viral-Specific Pre-initiation Complex Is Key.Front. Microbiol. 2016; 7: 869Crossref PubMed Scopus (71) Google Scholar). Targeting these less diverse vTRs using small-molecule or genome editing strategies might therefore yield more effective therapies. vTR proteins demonstrate a remarkable degree of structural diversity (Figure S2). To date, less than 12% of vTRs have been characterized at the structural level (Table S2). Many of the characterized vTRs have unique protein structures, with no detectable homology to any other virus or host protein (Yin and Fischer, 2008Yin Y. Fischer D. Identification and investigation of ORFans in the viral world.BMC Genomics. 2008; 9: 24Crossref PubMed Scopus (74) Google Scholar). In a few cases, similar folds can be observed across viral species, such as the DBDs of E2 (HPV) and EBNA1 (EBV), which consist of two beta-alpha-beta repeats of approximately equal length (Bussiere et al., 1998Bussiere D.E. Kong X. Egan D.A. Walter K. Holzman T.F. Lindh F. Robins T. Giranda V.L. Structure of the E2 DNA-binding domain from human papillomavirus serotype 31 at 2.4 A.Acta Crystallogr. D Biol. Crystallogr. 1998; 54: 1367-1376Crossref PubMed Google Scholar). Because there is no detectable structural similarity between most vTRs and human proteins, their novel structures may provide an avenue for developing drugs with high selectivity for disrupting their transcriptional activity. For example, an inhibitory peptide against EBNA2 was found to reduce cell growth and viability of EBV-infected cells (Farrell et al., 2004Farrell C.J. Lee J.M. Shin E.C. Cebrat M. Cole P.A. Hayward S.D. Inhibition of Epstein-Barr virus-induced growth proliferation by a nuclear antigen EBNA2-TAT peptide.Proc. Natl. Acad. Sci. USA. 2004; 101: 4625-4630Crossref PubMed Scopus (47) Google Scholar), providing proof-of-concept that vTRs can be suitable drug targets to fight viral infections and their pathogenic effects. Despite overall low sequence conservation, some DBD structures are shared among a subset of vTRs (Figure S2). One such domain is the basic leucine zipper (bZIP), which is also present in many eukaryotic TFs (Vinson et al., 1989Vinson C.R. Sigler P.B. McKnight S.L. Scissors-grip model for DNA recognition by a family of leucine zipper proteins.Science. 1989; 246: 911-916Crossref PubMed Scopus (733) Google Scholar). bZIP-containing vTRs have been identified in a range of human viruses, including K8 (KSHV), Zta (EBV), and HBZ (human T cell leukemia virus 1 [HTLV-1]) and can bind DNA as homodimers or as heterodimers with host bZIP proteins (Basbous et al., 2003Basbous J. Arpin C. Gaudray G. Piechaczyk M. Devaux C. Mesnard J.M. The HBZ factor of human T-cell leukemia virus type I dimerizes with transcription factors JunB and c-Jun and modulates their transcriptional activity.J. Biol. Chem. 2003; 278: 43620-43627Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar; Ellison et al., 2009Ellison T.J. Izumiya Y. Izumiya C. Luciw P.A. Kung H.J. A comprehensive analysis of recruitment and transactivation potential of K-Rta and K-bZIP during reactivation of Kaposi’s sarcoma-associated herpesvirus.Virology. 2009; 387: 76-88Crossref PubMed Scopus (44) Google Scholar; Lieberman and Berk, 1990Lieberman P.M. Berk A.J. In vitro transcriptional activation, dimerization, and DNA-binding specificity of the Epstein-Barr virus Zta protein.J. Virol. 1990; 64: 2560-2568Crossref PubMed Google Scholar). The interferon regulatory factor (IRF) domain, which is present in host TFs that regulate antiviral responses, is also found in multiple vTRs (Figure S2). For example, the KSHV genome encodes four proteins, vIRF1–vIRF4, that perturb antiviral responses by competing for host IRF DNA binding sites, heterodimerizing with host IRFs, and competing for host coactivators such as CREBBP and EP300 (Offermann, 2007Offermann M.K. Kaposi sarcoma herpesvirus-encoded interferon regulator factors.Curr. Top. Microbiol. Immunol. 2007; 312: 185-209PubMed Google Scholar). In summary, vTRs come from a wide range of structural classes, enabling a diverse range of mechanisms used to interact with the host genome and host proteins. The different classes of viruses coordinate genome replication, virion assembly, and entry and exit from latency by precisely regulating the timing of viral gene expression using different types of vTRs. vTRs from DNA viruses directly or indirectly bind to viral gene promoters to regulate multiple stages in the viral replication cycle, including establishment and maintenance of latency by episome maintenance proteins (De Leo et al., 2020De Leo A. Calderon A. Lieberman P.M. Control of Viral Latency by Episome Maintenance Proteins.Trends Microbiol. 2020; 28: 150-162Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). vTRs from retroviruses, such as Tat (HIV), Bel-1 (human spumaretrovirus), and Tax (human T cell leukemia virus [HTLV]), work with host proteins to activate the expression of viral genes and viral RNA replication from the integrated provirus as a mechanism to regulate the exit from latency. Positive and negative strand RNA viruses use vTRs that directly or indirectly bind to RNA, such as N (coronavirus), NP (Ebola virus), and phosphoprotein (measles virus), to regulate the expression of viral genes and the replication of the viral genome. DNA virus vTRs often control a complex cascade of molecular events in the viral replication cycle. “Early class” genes generally encode proteins involved in DNA replication, nucleotide biosynthesis, regulation of intermediate and late viral genes, and immune evasion. “Intermediate” and “late class” genes encode proteins involved in virion morphogenesis and assembly. In DNA viruses with a compact genome, one or a few vTRs work with host TFs and cofactors to control the expression of all viral genes. For example, polyomavirus SV40 large T-antigen is responsible for the regulation of both early and late gene transcription (Kriegler et al., 1984Kriegler M. Perez C.F. Hardy C. Botchan M. Transformation mediated by the SV40 T antigens: separation of the overlapping SV40 early genes with a retroviral vector.Cell. 1984; 38: 483-491Abstract Full Text PDF PubMed Scopus (51) Google Scholar). Other DNA viruses exhibit a strictly regulated temporal cascade of gene expression involving different vTRs. For example, the UL48 (HSV-1) protein induces the expression of the immediate early vTR RS1, which in turn induces the expression of UL29, an important vTR for maintaining the highly ordered downstream cascade of viral gene expression (Weller and Coen, 2012Weller S.K. Coen D.M. Herpes simplex viruses: mechanisms of DNA replication.Cold Spring Harb. Perspect. Biol. 2012; 4: a013011Crossref PubMed Scopus (153) Google Scholar). Some vTRs function as a multiprotein complex together with other viral proteins. This is the case for the transcription initiation complex vPIC in EBV, which is comprised of BcRF1, a homolog of archaeal TATA-box-binding protein (TBP) that interacts with TATT sequences in EBV late gene promoters, and BVLF1, BFRF2, BGLF3, BDLF4, and BDLF3.5, which are involved in RNA Pol II recruitment and transcriptional elongation (Gruffat et al., 2016Gruffat H. Marchione R. Manet E. Herpesvirus Late Gene Expression: A Viral-Specific Pre-initiation Complex Is Key.Front. Microbiol. 2016; 7: 869Crossref PubMed Scopus (71) Google Scholar). The vPIC complex has also been identified in other beta and gamma herpesviruses, such as KSHV (Nandakumar and Glaunsinger, 2019Nandakumar D. Glaunsinger B. An integrative approach identifies direct targets of the late viral transcription complex and an expanded promoter recognition motif in Kaposi’s sarcoma-associated herpesvirus.PLoS Pathog. 2019; 15: e1007774Crossref PubMed Scopus (10) Google Scholar), but not in alpha herpesviruses, and constitutes a shared mechanism for regulating the expression of viral late genes. Overall, viruses control the expression of their own genes through mechanisms ranging from simple (e.g., one vTR controlling a few genes) to complex (e.g., tightly controlled transcriptional cascades, vTR-host protein interactions, and multi-protein complexes). In addition to regulating viral genes, DNA and RNA virus vTRs can modulate the expression of host genes that play important roles in the immune system, cell cycle, metabolism, and other processes (Figure 3A). This can be achieved through direct or indirect vTR binding to cellular target gene regulatory regions, the initiation of global changes in chromatin structure and condensation, or by interfering with host TF activities. For example, UL54 (HSV-1) and vIRF1-3 (KSHV) inhibit type I interferon production and/or the activation of interferon effector pathways, which constitute key antiviral mechanisms (Chiang and Liu, 2019Chiang H.S. Liu H.M. The Molecular Basis of Viral Inhibition of IRF- and STAT-Dependent Immune Responses.Front. Immunol. 2019; 9: 3086Crossref PubMed Scopus (65) Google Scholar). In addition to blocking interferon pathways, a subset of vTRs can induce an immunosuppressive state by modulating pro- or anti-inflammatory genes. For example, Zta (EBV) binds to the host genome, activating the expression of immunosuppressive genes such as TGFBI and TGFB1, and downregulating the expression of genes that mediate immune responses such as TLR9, IFI6, and IL23A (Cayrol and Flemington, 1995Cayrol C. Flemington E.K. Identification of cellular target genes of the Epstein-Barr virus transactivator Zta: activation of transforming growth factor beta igh3 (TGF-beta igh3) and TGF-beta 1.J. Virol. 1995; 69: 4206-4212Crossref PubMed Google Scholar; Ramasubramanyan et al., 2015Ramasubramanyan S. Osborn K. Al-Mohammad R. Naranjo Perez-Fernandez I.B. Zuo J. Balan N. Godfrey A. Patel H. Peters G. Rowe M. et al.Epstein-Barr virus transcription factor Zta acts through distal regulatory elements to directly control cellular gene expression.Nucleic Acids Res. 2015; 43: 3563-3577Crossref PubMed Scopus (29) Google Scholar). Other vTRs activate the production of IL10 to mediate immunosuppression. For example, Rta (KSHV) induces IL10 production through interactions with the host TFs SP1 and SP3 (Miyazawa et al., 2018Miyazawa M. Noguchi K. Kujirai M. Katayama K. Yamagoe S. Sugimoto Y. IL-10 promoter transactivation by the viral K-RTA protein involves the host-cell transcription factors, specificity proteins 1 and 3.J. Biol. Chem. 2018; 293: 662-676Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). Other vTRs contribute to viral pathogenesis by increasing the expression of pro-inflammatory mediators. For example, N from SARS-CoV induces lung inflammation by activating the PTGS2 promoter through interactions with nuclear factor κB (NF-κB) and C/EBP binding sites (Yan et al., 2006Yan X. Hao Q. Mu Y. Timani K.A. Ye L. Zhu Y. Wu J. Nucleocapsid protein of SARS-CoV activates the expression of cyclooxygenase-2 by binding directly to regulatory elements for nuclear factor-kappa B and CCAAT/enhancer binding protein.Int. J. Biochem. Cell Biol. 2006; 38: 1417-1428Crossref PubMed Scopus (108) Google Scholar). By altering the expression levels of host immune genes through a variety of mechanisms, vTRs are key to host evasion mechanisms and pathogenesis. Viruses can also modulate the cell cycle and induce cellular reprogramming to initiate cellular conditions that are beneficial for replication. For example, E1A (adenovirus) can epigenetically reprogram quiescent human cells by interacting with retinoblastoma proteins and EP300, activating the transcription of cell cycle and proliferation genes, and repressing the transcription of antiviral genes and genes involved in differentiation and development (Ferrari et al., 2008Ferrari R. Pellegrini M. Horwitz G.A. Xie W. Berk A.J. Kurdistani S.K. Epigenetic reprogramming by adenovirus e1a.Science. 2008; 321: 1086-1088Crossref PubMed Scopus (183) Google Scholar). vTRs can also promote cellular transformation by regulating the expression of oncogenes or tumor suppressor genes. For example, vTRs encoded by several viruses target TERT (EBV, hepatitis B virus [HBV], hepatitis C virus [HCV], HPV, HTLV-1, and KSHV) and MYC (adenovirus, EBV, HPV, KSHV, and HPV) (Bellon and Nicot, 2008Bellon M. Nicot C. Regulation of telomerase and telomeres: human tumor viruses take control.J. Natl. Cancer Inst. 2008; 100: 98-108Crossref PubMed Scopus (82) Google Scholar; Mesri et al., 2014Mesri E.A. Feitelson M.A. Munger K. Human viral oncogenesis: a cancer hallmarks analysis.Cell Host Microbe. 2014; 15: 266-282Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar). vTRs such as HBx (HBV) and E1A (adenovirus), can also rewire m" @default.
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• W3041760426 title "Human Virus Transcriptional Regulators" @default.
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