scholarly journals Independent Contributions of Polyomavirus Middle T and Small T to the Regulation of Early and Late Gene Expression and DNA Replication

2006 ◽  
Vol 80 (15) ◽  
pp. 7295-7307 ◽  
Author(s):  
Li Chen ◽  
Xiaoyu Wang ◽  
Michele M. Fluck
Keyword(s):  
Gene Expression ◽  
Dna Replication ◽  
Signaling Pathways ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Phosphatidylinositol 3 Kinase ◽  
Late Gene Expression ◽  
Respective Contribution ◽  
Mouse Cells ◽  
The Individual

ABSTRACT We previously showed that murine polyomavirus mutants that lack both middle T (MT) and small T (ST) functions have a severe pleiotropic defect in early and late viral gene expression as well as genome amplification. The respective contribution of MT and ST to this phenotype was unclear. This work separates the roles of MT and ST in both permissive mouse cells and nonpermissive rat cells. It demonstrates for the first time a role for both proteins. To gain insight into the signaling pathways that might be required, we focused on MT and its mutants. The results show that each of the major MT signaling connections, Shc, phosphatidylinositol 3′-kinase, and phospholipase C γ1, could contribute in an additive way. Unexpectedly, a mutant lacking all these connections because the three major tyrosines had been converted to phenylalanine retained some activity. A mutant in which all six MT C-terminal tyrosines had been mutated was inactive. This suggests a novel signaling pathway for MT that uses the minor tyrosines. What is common to ST and the individual MT signaling pathways is the ability to signal to the polyomavirus enhancer, in particular to the crucial AP-1 and PEA3/ets binding sites. This connection explains the pleiotropy of MT and ST effects on transcription and DNA replication.

scholarly journals Lytic infection of permissive cells with human cytomegalovirus is regulated by an intrinsic ‘pre-immediate-early’ repression of viral gene expression mediated by histone post-translational modification

2009 ◽  
Vol 90 (10) ◽  
pp. 2364-2374 ◽  
Author(s):  
Ian J. Groves ◽  
Matthew B. Reeves ◽  
John H. Sinclair
Keyword(s):  
Gene Expression ◽  
Human Cytomegalovirus ◽  
Chromatin Structure ◽  
Viral Gene Expression ◽  
Lytic Infection ◽  
Immediate Early ◽  
Late Gene ◽  
Viral Gene ◽  
Gene Promoters ◽  
Late Gene Expression

Human cytomegalovirus (HCMV) lytic gene expression occurs in a regulated cascade, initiated by expression of the viral major immediate-early (IE) proteins. Transcribed from the major IE promoter (MIEP), the major IE genes regulate viral early and late gene expression. This study found that a substantial proportion of infecting viral genomes became associated with histones immediately upon infection of permissive fibroblasts at low m.o.i. and these histones bore markers of repressed chromatin. As infection progressed, however, the viral MIEP became associated with histone marks, which correlate with the known transcriptional activity of the MIEP at IE time points. Interestingly, this chromatin-mediated repression of the MIEP at ‘pre-IE’ times of infection could be overcome by inhibition of histone deacetylases, as well as by infection at high m.o.i., and resulted in a temporal advance of the infection cycle by inducing premature viral early and late gene expression and DNA replication. As well as the MIEP, and consistent with previous observations, the viral early and late promoters were also initially associated with repressive chromatin. However, changes in histone modifications around these promoters also occurred as infection progressed, and this correlated with the known temporal regulation of the viral early and late gene expression cascade. These data argue that the chromatin structure of all classes of viral genes are initially repressed on infection of permissive cells and that the chromatin structure of HCMV gene promoters plays an important role in regulating the time course of viral gene expression during lytic infection.

T4 DNA replication and viral gene expression

1971 ◽  
Vol 61 (2) ◽  
pp. 357-367 ◽  
Author(s):  
A. Cascino ◽  
E.P. Geiduschek ◽  
R.L. Cafferata ◽  
R. Haselkorn
Keyword(s):  
Gene Expression ◽  
Dna Replication ◽  
Viral Gene Expression ◽  
Viral Gene

scholarly journals Kaposi's Sarcoma-Associated Herpesvirus K-bZIP Protein Is Necessary for Lytic Viral Gene Expression, DNA Replication, and Virion Production in Primary Effusion Lymphoma Cell Lines

2009 ◽  
Vol 83 (11) ◽  
pp. 5869-5880 ◽  
Author(s):  
Sylvain Lefort ◽  
Louis Flamand
Keyword(s):  
Gene Expression ◽  
Dna Replication ◽  
Kaposi's Sarcoma ◽  
Viral Gene Expression ◽  
Kaposi’S Sarcoma ◽  
Viral Gene ◽  
Viral Dna ◽  
Viral Dna Replication ◽  
Virion Production ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of three human proliferative disorders, namely, Kaposi's sarcoma, primary effusion lymphomas (PEL), and multicentric Castleman's disease. Lytic DNA replication of KSHV, which is essential for viral propagation, requires the binding of at least two KSHV proteins, replication and transactivation activator (RTA) and K-bZIP, on the lytic origin of replication. Moreover, K-bZIP physically interacts with RTA and represses its transactivation activity on several viral promoters in transient transfection assays. To evaluate the physiological roles of K-bZIP in the context of PEL, we generated BCBL-1 cells with a tetracycline (Tet)-inducible small hairpin RNA (shRNA) directed against the K8 mRNA to knock down K-bZIP expression at different points during KSHV's life cycle. Using this model, we demonstrate that in the absence of K-bZIP expression, dramatic decreases in orf50, orf57, and orf26 transcript expression are observed. Similar effects were seen at the protein level for RTA (immediate-early protein) and K8.1 (late protein) expression. Interestingly, a direct correlation between K-bZIP levels and viral lytic mRNAs was noticed. As a consequence of K-bZIP knockdown, viral DNA replication and virion production were severely impaired. The same effects were observed following knockdown of K-bZIP in another PEL cell line, BC3. Finally, using shRNA-K8-inducible 293 cells, we report that de novo synthesis of K-bZIP is not necessary for initiation of infection and latency establishment. These data support the concept that K-bZIP is essential for lytic viral gene expression, viral DNA replication, and virus propagation in PEL cells.

scholarly journals Inhibition of Hepatitis B Virus Gene Expression and Replication by Hepatocyte Nuclear Factor 6

2015 ◽  
Vol 89 (8) ◽  
pp. 4345-4355 ◽  
Author(s):  
Ruidong Hao ◽  
Jing He ◽  
Xing Liu ◽  
Guozhen Gao ◽  
Dan Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatitis B Virus ◽  
Dna Replication ◽  
Hepatitis B ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Gender Dimorphism ◽  
B Virus

ABSTRACTHepatitis B virus (HBV), a small enveloped DNA virus, chronically infects more than 350 million people worldwide and causes liver diseases from hepatitis to cirrhosis and liver cancer. Here, we report that hepatocyte nuclear factor 6 (HNF6), a liver-enriched transcription factor, can inhibit HBV gene expression and DNA replication. Overexpression of HNF6 inhibited, while knockdown of HNF6 expression enhanced, HBV gene expression and replication in hepatoma cells. Mechanistically, the SP2 promoter was inhibited by HNF6, which partly accounts for the inhibition on S mRNA. Detailed analysis showed that aciselement on the HBV genome (nucleotides [nt] 3009 to 3019) was responsible for the inhibition of the SP2 promoter by HNF6. Moreover, further analysis showed that HNF6 reduced viral pregenomic RNA (pgRNA) posttranscriptionally via accelerating the degradation of HBV pgRNA independent of La protein. Furthermore, by using truncated mutation experiments, we demonstrated that the N-terminal region of HNF6 was responsible for its inhibitory effects. Importantly, introduction of an HNF6 expression construct with the HBV genome into the mouse liver using hydrodynamic injection resulted in a significant reduction in viral gene expression and DNA replication. Overall, our data demonstrated that HNF6 is a novel host factor that can restrict HBV replication via both transcriptional and posttranscriptional mechanisms.IMPORTANCEHBV is a major human pathogen whose replication is regulated by host factors. Liver-enriched transcription factors are critical for many liver functions, including metabolism, development, and cell proliferation, and some of them have been shown to regulate HBV gene expression or replication in different manners. In this study, we showed that HNF6 could inhibit the gene expression and DNA replication of HBV via both transcriptional and posttranscriptional mechanisms. As HNF6 is differentially expressed in men and women, the current results may suggest a role of HNF6 in the gender dimorphism of HBV infection.

scholarly journals Sp1 Sites in the Noncoding Control Region of BK Polyomavirus Are Key Regulators of Bidirectional Viral Early and Late Gene Expression

2015 ◽  
Vol 89 (6) ◽  
pp. 3396-3411 ◽  
Author(s):  
Tobias Bethge ◽  
Helen A. Hachemi ◽  
Julia Manzetti ◽  
Rainer Gosert ◽  
Walter Schaffner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Gene Expression ◽  
Early Gene ◽  
Late Gene ◽  
Viral Gene ◽  
Late Gene Expression ◽  
Early Gene Expression ◽  
Bk Polyomavirus ◽  
Group 2 ◽  
Group 1

ABSTRACTIn kidney transplant patients with BK polyomavirus (BKPyV) nephropathy, viral variants arise bearing rearranged noncoding control regions (rr-NCCRs) that increase viral early gene expression, replicative fitness, and cytopathology.rr-NCCRs result from various deletions and duplications of archetype NCCR (ww-NCCR) sequences, which alter transcription factor binding sites (TFBS). However, the role of specific TFBS is unclear. We inactivated 28 TFBS in the archetype NCCR by selective point mutations and examined viral gene expression in bidirectional reporter constructs. Compared to the archetype, group 1 mutations increased viral early gene expression similar torr-NCCR and resulted from inactivating oneSp1or oneEts1TFBS near the late transcription start site (TSS). Group 2 mutations conferred intermediate early gene activation and affected NF1, YY1, and p53 sites between early and late TSS. Group 3 mutations decreased early and late gene expression and included two otherSp1sites near the early TSS. Recombinant viruses bearing group 1 NCCRs showed increased replication in human renal epithelial cells similar to clinicalrr-NCCR variants. Group 2 and 3 viruses showed intermediate or no replication, respectively. A literature search revealed unnoticed group 1 mutations in BKPyV nephropathy, hemorrhagic cystitis, and disseminated disease.IMPORTANCEThe NCCRs of polyomaviruses mediate silent persistence of the viral genome as well as the appropriately timed (re)activation of the viral life cycle. This study indicates that the basal BKPyV NCCR is critically controlled by a hierarchy of single TFBS in the archetype NCCR that direct, modulate, and execute the bidirectional early and late viral gene expression. The results provide new insights into how BKPyV NCCR functions as a viral sensor of host cell signals and shed new light on how transcription factors like Sp1 control bidirectional viral gene expression and contribute to replication and pathology.

scholarly journals Temporal Dynamics of HCMV Gene Expression in Lytic and Latent Infections

2021 ◽  
Author(s):  
Batsheva Rozman ◽  
Yaarit Kitsberg ◽  
Aharon Nachshon ◽  
Michal Schwartz ◽  
Noam Stern-Ginossar
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Dna Replication ◽  
Latent Infection ◽  
Viral Gene Expression ◽  
Productive Infection ◽  
Viral Gene ◽  
Viral Dna ◽  
Viral Dna Replication ◽  
Viral Genes

Primary infection with Human cytomegalovirus (HCMV) results in a persistent lifelong infection due to its ability to establish latent infection. During productive HCMV infection, viral genes are expressed in a coordinated cascade that is characteristic of all herpesviruses and traditionally relies on the dependencies of viral genes on protein synthesis and viral DNA replication. In contrast, the transcriptional landscape associated with HCMV latency is still disputed and poorly understood. Here, we examine viral transcriptomic dynamics during the establishment of both productive and latent HCMV infections. These temporal measurements reveal that viral gene expression dynamics along productive infection and their dependencies on protein synthesis and viral DNA replication, do not fully align. This illustrates that the regulation of herpesvirus genes does not represent a simple sequential transcriptional cascade and surprisingly many viral genes are regulated by multiple independent modules. Using our improved classification of viral gene expression kinetics in conjunction with transcriptome-wide measurements of the effects of a wide array of chromatin modifiers, we unbiasedly show that a defining characteristic of latent cells is the unique repression of immediate early (IE) genes. In particular, we demonstrate that IE1 (a central IE protein) expression is the principal barrier for achieving a full productive cycle. Altogether, our findings provide an unbiased and elaborate definition of HCMV gene expression in lytic and latent infection states.

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