Epigenetics and animal virus infections (original) (raw)
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Host-virus interactions: from the perspectives of epigenetics
Reviews in Medical Virology, 2014
Chromatin structure and histone modifications play key roles in gene regulation. Some virus genomes are organized into chromatin-like structure, which undergoes different histone modifications facilitating complex functions in virus life cycles including replication. Here, we present a comprehensive summary of recent research in this field regarding the interaction between viruses and host epigenetic factors with emphasis on how chromatin modifications affect viral gene expression and virus infection. We also describe the strategies employed by viruses to manipulate the host epigenetic program to facilitate virus replication as well as the underlying mechanisms. Together, knowledge from this field not only generates novel insights into virus life cycles but may also have important therapeutic implications.
Epigenetic control of viral life-cycle by a DNA-methylation dependent transcription factor
2011
Epstein-Barr virus (EBV) encoded transcription factor Zta (BZLF1, ZEBRA, EB1) is the prototype of a class of transcription factor (including C/EBPalpha) that interact with CpG-containing DNA response elements in a methylation-dependent manner. The EBV genome undergoes a biphasic methylation cycle; it is extensively methylated during viral latency but is reset to an unmethylated state following viral lytic replication. Zta is expressed transiently following infection and again during the switch between latency and lytic replication. The requirement for CpG-methylation at critical Zta response elements (ZREs) has been proposed to regulate EBV replication, specifically it could aid the activation of viral lytic gene expression from silenced promoters on the methylated genome during latency in addition to preventing full lytic reactivation from the non-methylated EBV genome immediately following infection. We developed a computational approach to predict the location of ZREs which we experimentally assessed using in vitro and in vivo DNA association assays. A remarkably different binding motif is apparent for the CpG and non-CpG ZREs. Computational prediction of the location of these binding motifs in EBV revealed that the majority of lytic cycle genes have at least one and many have multiple copies of methylation-dependent CpG ZREs within their promoters. This suggests that the abundance of Zta protein coupled with the methylation status of the EBV genome act together to co-ordinate the expression of lytic cycle genes at the majority of EBV promoters.
Proceedings of the National Academy of Sciences, 1981
The Mov-3 substrain of mice carries Moloney murine leukemia virus as a Mendelian gene in its germ line. All mice segregating the Mov-3 locus activate virus and develop viremia and leukemia. The integrated provirus (i.e., Mov-3 locus) was molecularly cloned from Mov-3 liver DNA as a 16.8 kilobase longEcoRI fragment. Comparison ofthe cloned and genomic Mov-3 specific EcoRI fragment by restriction enzyme analysis showed no differences in the size ofthe fragments, indicating that no major sequence rearrangements occurred during cloning. The genomic and cloned Mov-3 DNAs were compared for methylation and infectivity. Analysis with Hha I showed that the genomic proviral and the flanking mouse sequences were methylated at cytosine residues, in contrast to the cloned Mov-3 locus. The cloned Mov-3 locus, however, was highly infectious in a transfection assay (1 x 10-5 plaque-forming unit per viral genome) in contrast to the genomic Mov-3 DNA (<10 per viral genome). Our results suggest that genes containing 5-methylcytosine are not expressed after transfection into susceptible cells and that removal of the methyl groups by molecular cloning in prokaryotes leads to expression generating infectious proviral DNA. If gene expression of transfected DNA is controlled by mechanisms that are relevant for gene expression in the animal, this suggests that DNA methylation may play a causative role in eukaryotic gene regulation.
Parvovirus B19 DNA CpG Dinucleotide Methylation and Epigenetic Regulation of Viral Expression
PLoS ONE, 2012
CpG DNA methylation is one of the main epigenetic modifications playing a role in the control of gene expression. For DNA viruses whose genome has the ability to integrate in the host genome or to maintain as a latent episome, a correlation has been found between the extent of DNA methylation and viral quiescence. No information is available for Parvovirus B19, a human pathogenic virus, which is capable of both lytic and persistent infections. Within Parvovirus B19 genome, the inverted terminal regions display all the characteristic signatures of a genomic CpG island; therefore we hypothesised a role of CpG dinucleotide methylation in the regulation of viral genome expression. The analysis of CpG dinucleotide methylation of Parvovirus B19 DNA was carried out by an aptly designed quantitative real-time PCR assay on bisulfitemodified DNA. The effects of CpG methylation on the regulation of viral genome expression were first investigated by transfection of either unmethylated or in vitro methylated viral DNA in a model cell line, showing that methylation of viral DNA was correlated to lower expression levels of the viral genome. Then, in the course of in vitro infections in different cellular environments, it was observed that absence of viral expression and genome replication were both correlated to increasing levels of CpG methylation of viral DNA. Finally, the presence of CpG methylation was documented in viral DNA present in bioptic samples, indicating the occurrence and a possible role of this epigenetic modification in the course of natural infections. The presence of an epigenetic level of regulation of viral genome expression, possibly correlated to the silencing of the viral genome and contributing to the maintenance of the virus in tissues, can be relevant to the balance and outcome of the different types of infection associated to Parvovirus B19.
Biochimica Et Biophysica Acta Gene Structure and Expression, 1989
Integrated adenovims type 12 (Adl2} genes in Adl2-transformed cell lines were investigated for chromatin structure, expression levels and states of DNA methylation. The E3 region in the Adl2-transformed cell line HAl2/7 is hypemtethylated and not expressed. The same region in the Adl2-tra~Mormed hamster cell lines T637 and A2497.3 is ~bed and undormethylated (Kruczek, !. and Dnerfler, W. (1982) EMBO J. 1, 409--414). There was no significant difference In the DNase I sensitivity of the E3 region when nuclei of the aforementioned cell lines were incubated with this nuclesse. In contrast, incubation of these nuclei with the restriction endo~uclease Pstl and subsequent cleavage of the DNA with BamHl generated an additional 0.9 kbp fragment in T637 and A2497-3 DNA which was not observed after treating HAI2/7 nuclei and DNA in the same way. This finding was interpreted as indicative of differences in the chromatin structure of the E3 region depending on its state of transcriptional activity and its level of methyintion. The E1 and major late promoter regions, which were transcriptionally active and inactive, respectively, in all three cell lines investigated, did not exhibit differences in sensitivity towards DNase I or Pat| treatment of nuclei. More refined technology will be required to compare the chromatin structure of active venus inactive genes.
Journal of Virology, 1982
The nature of Moloney murine leukemia virus (M-MuLV)-specific proviral DNA in exogenously infected mouse cells was studied. M-MuLV clone A9 cells, NIH-3T3 fibroblasts productively infected with M-MuLV, were used. These cells contain 10 to 15 copies of M-MuLV proviral DNA. The state of methylation of M-MuLV proviral DNA was examined by cleaving A9 cell DNA with restriction endonucleases which have the dinucleotide CpG in their cleavage sequences. Analysis with such enzymes, which recognized nine different sites in M-MuLV DNA, indicated that most if not all of the M-MuLV proviruses in A9 cells were completely unmethylated. An individual proviral integration was examined, using as probe adjacent single-copy cellular sequences. These sequences were obtained from a lambda phage recombinant clone containing an M-MuLV provirus from the A9 cells. This individual integration also showed no detectable methylation. In contrast, endogenous MuLV-related sequences present in NIH-3T3 cells before ...
Viral genome methylation as an epigenetic defense against geminiviruses
Journal of virology, 2008
Geminiviruses encapsidate single-stranded DNA genomes that replicate in plant cell nuclei through doublestranded DNA intermediates that associate with cellular histone proteins to form minichromosomes. Like most plant viruses, geminiviruses are targeted by RNA silencing and encode suppressor proteins such as AL2 and L2 to counter this defense. These related proteins can suppress silencing by multiple mechanisms, one of which involves interacting with and inhibiting adenosine kinase (ADK), a cellular enzyme associated with the methyl cycle that generates S-adenosyl-methionine, an essential methyltransferase cofactor. Thus, we hypothesized that the viral genome is targeted by small-RNA-directed methylation. Here, we show that Arabidopsis plants with mutations in genes encoding cytosine or histone H3 lysine 9 (H3K9) methyltransferases, RNA-directed methylation pathway components, or ADK are hypersensitive to geminivirus infection. We also demonstrate that viral DNA and associated histone H3 are methylated in infected plants and that cytosine methylation levels are significantly reduced in viral DNA isolated from methylation-deficient mutants. Finally, we demonstrate that Beet curly top virus L2 ؊ mutant DNA present in tissues that have recovered from infection is hypermethylated and that host recovery requires AGO4, a component of the RNA-directed methylation pathway. We propose that plants use chromatin methylation as a defense against DNA viruses, which geminiviruses counter by inhibiting global methylation. In addition, our results establish that geminiviruses can be useful models for genome methylation in plants and suggest that there are redundant pathways leading to cytosine methylation.
Reorganization of the host epigenome by a viral oncogene
Genome Research, 2012
Adenovirus small e1a oncoprotein causes~70% reduction in cellular levels of histone H3 lysine 18 acetylation (H3K18ac). It is unclear, however, where this dramatic reduction occurs genome-wide. ChIP-sequencing revealed that by 24 h after expression, e1a erases 95% of H3K18ac peaks in normal, contact-inhibited fibroblasts and replaces them with one-third as many at new genomic locations. The H3K18ac peaks at promoters and intergenic regions of genes with fibroblast-related functions are eliminated after infection, and new H3K18ac peaks are established at promoters of highly induced genes that regulate cell cycling and at new putative enhancers. Strikingly, the regions bound by the retinoblastoma family of proteins in contact-inhibited fibroblasts gain new peaks of H3K18ac in the e1a-expressing cells, including 55% of RB1bound loci. In contrast, over half of H3K9ac peaks are similarly distributed before and after infection, independently of RB1. The strategic redistribution of H3K18ac by e1a highlights the importance of this modification for transcriptional activation and cellular transformation as well as functional differences between the RB-family member proteins.