Parvovirus Nonstructural Proteins Induce an Epigenetic Modification through Histone Acetylation in Host Genes and Revert Tumor Malignancy to Benignancy

Iseki, Hiroyoshi; Shimizukawa, Rie; Sugiyama, Fumihiro; Kunita, Satoshi; Iwama, Atsushi; Onodera, Masafumi; Nakauchi, Hiromitsu; Yagami, Ken‐ichi

doi:10.1128/jvi.79.14.8886-8893.2005

Cited by 18 publications

(17 citation statements)

References 45 publications

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“…This interaction likely is caused by the accumulation of NS1 on viral genomes because of its involvement in transcription and replication (52)(53)(54). NS1 of autonomous parvoviruses not only controls the viral activities but also regulates host gene expression through histone acetylation in cancer cells by recruiting innate proteins with HAT activity (55,56). To date, evidence for the involvement of NS1 in the regulation of histone acetylation on parvoviral promoters has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Promoter-Targeted Histone Acetylation of Chromatinized Parvoviral Genome Is Essential for the Progress of Infection

Mäntylä

Salokas

Oittinen

et al. 2016

J Virol

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The association of host histones with parvoviral DNA is poorly understood. We analyzed the chromatinization and histone acetylation of canine parvovirus DNA during infection by confocal imaging and in situ proximity ligation assay combined with chromatin immunoprecipitation and high-throughput sequencing. We found that during late infection, parvovirus replication bodies were rich in histones bearing modifications characteristic of transcriptionally active chromatin, i.e., histone H3 lysine 27 acetylation (H3K27ac). H3K27ac, in particular, was located in close proximity to the viral DNA-binding protein NS1. Importantly, our results show for the first time that in the chromatinized parvoviral genome, the two viral promoters in particular were rich in H3K27ac. Histone acetyltransferase (HAT) inhibitors efficiently interfered with the expression of viral proteins and infection progress. Altogether, our data suggest that the acetylation of histones on parvoviral DNA is essential for viral gene expression and the completion of the viral life cycle. IMPORTANCEViral DNA introduced into cell nuclei is exposed to cellular responses to foreign DNA, including chromatinization and epigenetic silencing, both of which determine the outcome of infection. How the incoming parvovirus resists cellular epigenetic downregulation of its genes is not understood. Here, the critical role of epigenetic modifications in the regulation of parvovirus infection was demonstrated. We showed for the first time that a successful parvovirus infection is characterized by the deposition of nucleosomes with active histone acetylation on the viral promoter areas. The results provide new insights into the regulation of parvoviral gene expression, which is an important aspect of the development of parvovirus-based virotherapy. N uclear chromatin is composed of DNA and histone proteins (1). The histone proteins assemble DNA into nucleosomes, the composition and spacing of which contribute to higher-order chromatin packing. The chromatin is organized into regions of less-condensed actively transcribed chromatin (euchromatin) and highly condensed transcriptionally repressed chromatin (heterochromatin). Epigenetic modifications of histone proteins have been shown to correlate with the spatial distribution of active and repressed chromatin (2, 3). The acetylation of lysine 9 or 27 of histone H3 (H3K9ac and H3K27ac, respectively) and trimethylation of lysine 4 (H3K4me3) correlate with transcriptional activity, while repressed chromatin is characterized by, e.g., trimethylation or dimethylation of the same H3 lysine residues (H3K9me3 and H3K27me3 as well as H3K9me2 and H3K27me2) (4-8).Foreign DNA introduced into mammalian cells can be recognized as a threat by the host cell. The cellular responses to the foreign DNA, such as viral DNA, include the chromatinization of the entering DNA, leading to its transcriptional silencing (9-11). How viruses resist cellular chromatinization and silencing is known for only a few viruses (9, 12, 13). These include h...

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Section: Discussionmentioning

confidence: 99%

Promoter-Targeted Histone Acetylation of Chromatinized Parvoviral Genome Is Essential for the Progress of Infection

Mäntylä

Salokas

Oittinen

et al. 2016

J Virol

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“…However, if a virus infection is present in a proportion of individuals in a colony, any resulting epigenetic changes may modify their response to environmental cues. Indeed, the nonstructural proteins of vertebrate parvoviruses can activate transcription factors (27) as well as induce epigenetic modification through histone acetylation (28).…”

Section: Discussionmentioning

confidence: 99%

Densovirus induces winged morphs in asexual clones of the rosy apple aphid, Dysaphis plantaginea

Ryabov

Keane

Naish

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Winged morphs of aphids are essential for their dispersal and survival. We discovered that the production of the winged morph in asexual clones of the rosy apple aphid, Dysaphis plantaginea, is dependent on their infection with a DNA virus, Dysaphis plantaginea densovirus (DplDNV). Virus-free clones of the rosy apple aphid, or clones infected singly with an RNA virus, rosy apple aphid virus (RAAV), did not produce the winged morph in response to crowding and poor plant quality. DplDNV infection results in a significant reduction in aphid reproduction rate, but such aphids can produce the winged morph, even at low insect density, which can fly and colonize neighboring plants. Aphids infected with DplDNV produce a proportion of virus-free aphids, which enables production of virus-free clonal lines after colonization of a new plant. Our data suggest that a mutualistic relationship exists between the rosy apple aphid and its viruses. Despite the negative impact of DplDNV on rosy apple aphid reproduction, this virus contributes to their survival by inducing wing development and promoting dispersal.development ͉ parvovirus ͉ pathogen ͉ polyphenism ͉ synergism P olyphenism, the production of discrete phenotypes based on the same genome, plays a central role in biology. The life cycle of alternate, cyclically parthenogenetic aphid species includes both a sexual generation and a number of asexual generations (1). In asexually reproducing clones, genetically identical aphids are either wingless (apterae) or winged (alate). Apterae show maximum fecundity, allowing rapid colony growth during long-day, warm conditions when resources are plentiful. Alates have lower fecundity, but are essential for dispersal and long-distance colonization of new plants (2, 3). Alates are generally not produced during the asexual phase of reproduction unless there is stress resulting from crowding or poor nutritional resources. The wing development in asexual clones of aphids is influenced by interactions between environmental and intrinsic factors. Several cues are implicated, including temperature, population density (tactile stimulation), nutritional quality of the host plant, and interactions with natural enemies and ants, although these cues are not universal inducers for wing development in asexual clones of different lines of the same aphid species (4, 5, 6). Increased production of alates was observed in Sitobion avenae reared on oats infected with barley yellow dwarf virus (7), although infection of Vicia faca with pea enation mosaic virus, bean yellow mosaic virus, or broad bean mottle virus did not increase production of alates in A. pisum (8). In addition, plant viruses have been reported to change aphid behavior as a result of physiological changes in the infected plants (reviewed in ref. 9).Several viruses of aphids have been characterized, including Myzus persicae densovirus (10); aphid lethal paralysis virus (11) and Rhopalosiphum padi virus (RhPV) (12), both members of the family Dicistroviridae; an iflavirus Brevicoryne brass...

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“…For example, histone acetylation (58,59) or methylation (60) has been found to play a role in regulating host gene expression following infection with various viruses in both rats and humans. By comparing HeLa and BeWo cells, Trejbalova and coworkers previously reported an inverse correlation between the levels of H3K9me3 in the 5= LTR of ERVWE1 and transcript levels (26).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Derepression of the ERVWE1 Locus following Influenza A Virus Infection

Nellåker

Sabunciyan

et al. 2014

J Virol

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Syncytin-1, a fusogenic protein encoded by a human endogenous retrovirus of the W family (HERV-W) element (ERVWE1), is expressed in the syncytiotrophoblast layer of the placenta. This locus is transcriptionally repressed in adult tissues through promoter CpG methylation and suppressive histone modifications. Whereas syncytin-1 appears to be crucial for the development and functioning of the human placenta, its ectopic expression has been associated with pathological conditions, such as multiple sclerosis and schizophrenia. We previously reported on the transactivation of HERV-W elements, including ERVWE1, during influenza A/WSN/33 virus infection in a range of human cell lines. Here we report the results of quantitative PCR analyses of transcripts encoding syncytin-1 in both cell lines and primary fibroblast cells. We observed that spliced ERVWE1 transcripts and those encoding the transcription factor glial cells missing 1 (GCM1), acting as an enhancer element upstream of ERVWE1, are prominently upregulated in response to influenza A/WSN/33 virus infection in nonplacental cells. Knockdown of GCM1 by small interfering RNA followed by infection suppressed the transactivation of ERVWE1. While the infection had no influence on CpG methylation in the ERVWE1 promoter, chromatin immunoprecipitation assays detected decreased H3K9 trimethylation (H3K9me3) and histone methyltransferase SETDB1 levels along with influenza virus proteins associated with ERVWE1 and other HERV-W loci in infected CCF-STTG1 cells. The present findings suggest that an exogenous influenza virus infection can transactivate ERVWE1 by increasing transcription of GCM1 and reducing H3K9me3 in this region and in other regions harboring HERV-W elements. IMPORTANCESyncytin-1, a protein encoded by the env gene in the HERV-W locus ERVWE1, appears to be crucial for the development and functioning of the human placenta and is transcriptionally repressed in nonplacental tissues. Nevertheless, its ectopic expression has been associated with pathological conditions, such as multiple sclerosis and schizophrenia. In the present paper, we report findings suggesting that an exogenous influenza A virus infection can transactivate ERVWE1 by increasing the transcription of GCM1 and reducing the repressive histone mark H3K9me3 in this region and in other regions harboring HERV-W elements. These observations have implications of potential relevance for viral pathogenesis and for conditions associated with the aberrant transcription of HERV-W loci.

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Parvovirus Nonstructural Proteins Induce an Epigenetic Modification through Histone Acetylation in Host Genes and Revert Tumor Malignancy to Benignancy

Cited by 18 publications

References 45 publications

Promoter-Targeted Histone Acetylation of Chromatinized Parvoviral Genome Is Essential for the Progress of Infection

Promoter-Targeted Histone Acetylation of Chromatinized Parvoviral Genome Is Essential for the Progress of Infection

Densovirus induces winged morphs in asexual clones of the rosy apple aphid, Dysaphis plantaginea

Transcriptional Derepression of the ERVWE1 Locus following Influenza A Virus Infection

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