Activation of latent Kaposi's sarcoma-associated herpesvirus by demethylation of the promoter of the lytic transactivator

Chen, Jiguo; Ueda, Keiji; Sakakibara, Shuhei; Okuno, Toshiomi; Parravicini, Carlo; Corbellino, Mario; Yamanishi, Koichi

doi:10.1073/pnas.051004198

Cited by 142 publications

(149 citation statements)

References 27 publications

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“…1; refs. 5,30). The extent of activation was similar to the levels of activation reported for other silenced genes with these drug treatments (31).…”

Section: B29 Gene Expression In Pel Is Activated By Demethylation Andsupporting

confidence: 79%

“…The loss of B lineage gene expression in PEL could be caused by DNA methylation and epigenetic silencing. In accord with this idea, ␥-herpesvirus genomes such as HHV-8, herpesvirus saimiri, and Epstein-Barr virus, are commonly methylated (4,5). The same mechanism(s) responsible for viral DNA methylation may also be involved in methylation and silencing of B lineage-specific genes in PEL.…”

mentioning

confidence: 96%

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C ^m C(A/T)GG DNA methylation in mature B cell lymphoma gene silencing

Malone¹,

Miner²,

Doerr³

et al. 2001

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

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P rimary effusion lymphoma (PEL) is an infrequent neoplasia of severe immunodeficiency and is usually observed in those with longstanding AIDS (1, 2). PEL exhibit features both in common with and distinct from other B cell neoplasms. Like myeloma, PEL arise from postgerminal center, developmentally mature B lymphocytes (1-3). Unlike myeloma, PEL grow in body cavities as liquid effusions, are almost always infected with human herpesvirus-8 (HHV-8) and lack expression of B-lineagespecific genes (reviewed in ref.2). The loss of B lineage gene expression in PEL could be caused by DNA methylation and epigenetic silencing. In accord with this idea, ␥-herpesvirus genomes such as HHV-8, herpesvirus saimiri, and Epstein-Barr virus, are commonly methylated (4, 5). The same mechanism(s) responsible for viral DNA methylation may also be involved in methylation and silencing of B lineage-specific genes in PEL.DNA methylation in mammalian cells largely occurs on cytosines in symmetric CpG dinucleotides and is associated with repressed gene transcription (6 -10). Methyl-binding domain proteins engage methylated CpG ( m CpG) and recruit histone deacetylase (HDAC) and transcriptional repressors to form stable repression complexes that induce local chromatin remodeling and gene silencing (11-16). Early mammalian embryos and germ cells, like plants and fungi, also methylate non-CpG cytosines (17-21). A recent report indicates that peripheral blood leukocytes may methylate the internal cytosine of symmetric CCTGG but not CCAGG motifs (22). However, little is known about the gene specificity, frequency, and functional significance of this latter type of symmetric non-CpG methylation.The B29 (Ig␤͞CD79b) component of the B cell surface receptor is encoded by the B29 gene and is absent in all PEL lines and some myelomas (1, 23). The B cell-specific B29 promoter is well characterized and provides an ideal model to analyze DNA methylation in B lineage gene silencing in PEL and myeloma. Early B cell factor (EBF), in concert with Octamer, Ets, Sp1, and Ikaros transcription factors, regulates B29 promoter activity in early B cell development, whereas non-EBF factors control B29 gene expression at later stages of B cell differentiation (24). The human B29 promoter contains 20 CpG dinucleotides and 6 CCAGG or CCTGG motifs within a 450-bp span (25). CpG dinucleotides are present in single Sp1 and EBF consensusbinding sites, whereas the CCAGG and CCTGG motifs are concentrated in a central promoter control region containing essential EBF sites.Here we report that the B29 promoter in PEL and nonexpressing myeloma cells is methylated at CpG and CC(A͞T)GG sites. Because the methylation pattern observed at these B29 promoter sites is similar to that reported in epigenetic retroviral silencing, we propose that B cell gene extinction occurs through a similar mechanism. We also find that CC(A͞T)GG methylation repressed B29 promoter activity and replaced transcription factors with new protein complexes. Materials and MethodsDNA Demethylation and HDAC In...

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“…1; refs. 5,30). The extent of activation was similar to the levels of activation reported for other silenced genes with these drug treatments (31).…”

Section: B29 Gene Expression In Pel Is Activated By Demethylation Andsupporting

confidence: 79%

mentioning

confidence: 96%

C ^m C(A/T)GG DNA methylation in mature B cell lymphoma gene silencing

Malone¹,

Miner²,

Doerr³

et al. 2001

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

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“…LANA is unmethylated (Chen et al, 2001) and is known to be associated with histone modifications and subsequent gene expression alterations in host and viral genes that contribute to viral oncogenesis (Sakakibara et al, 2004;Lu et al, 2006;Stuber et al, 2007). It has also been shown that the recruitment of a de novo methyltransferase (DNMT3b) causes downregulation of genes such as cadherin 13 and TGF-b by promoter methylation (Shamay et al, 2006;Di Bartolo et al, 2008).…”

Section: Viral Epigenomes In Human Tumorigenesis Af Fernandez and M Ementioning

confidence: 99%

“…During latency, ORF50 is repressed and the direct or indirect effects of LANA and/or DNA methylation of this gene promoter participate in the regulation of its expression (Chen et al, 2001;Lu et al, 2006;Li et al, 2008;Gray et al, 2009).…”

Section: Viral Epigenomes In Human Tumorigenesis Af Fernandez and M Ementioning

confidence: 99%

Viral epigenomes in human tumorigenesis

Fernández

Esteller

2010

Oncogene

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Viruses are associated with 15-20% of human cancers worldwide. In the last century, many studies were directed towards elucidating the molecular mechanisms and genetic alterations by which viruses cause cancer. The importance of epigenetics in the regulation of gene expression has prompted the investigation of virus and host interactions not only at the genetic level but also at the epigenetic level. In this study, we summarize the published epigenetic information relating to the genomes of viruses directly or indirectly associated with the establishment of tumorigenic processes. We also review aspects such as viral replication and latency associated with epigenetic changes and summarize what is known about epigenetic alterations in host genomes and the implications of these for the tumoral process. The advances made in characterizing epigenetic features in cancer-causing viruses have improved our understanding of their functional mechanisms. Knowledge of the epigenetic changes that occur in the genome of these viruses should provide us with markers for following cancer progression, as well as new tools for cancer therapy.

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“…Recently, Chen et al (2001) have proposed another mechanism that may regulate RTA expression. Methylation of CpG dinucleotide sequences within promoter regions is generally associated with transcriptional quiescence (Figure 4).…”

Section: The Autoregulation Of Rta Expressionmentioning

confidence: 99%

The role of Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8 regulator of transcription activation (RTA) in control of gene expression

2003

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The mechanisms that control the replication state, latency versus lytic, of human herpesviruses have been under intense investigations. Here we summarize some of the recent findings that help define such mechanisms for Kaposi's sarcoma-associated herpesvirus/human herpesvirus type 8 (KSHV/HHV-8). For HHV-8, the viral regulator of transcription activation (RTA) is a key mediator of the switch from latency to lytic gene expression in infected cells. RTA is necessary and sufficient to drive HHV-8 lytic replication and the production of viral progeny. The RTA is an immediateearly gene product, it is the initial activator of expression of a multitude of viral and cellular genes that have been implicated in the replication of HHV-8 and pathogenesis of KS. Interactions of RTA with a number of viral promoters, and with a number of transcription factors or transcriptional co-activators are highlighted. Modulation of transactivation, through alternate RTA-protein, or RTA-promoter interactions, is hypothesisized to participate in the selective tissue tropism and differential pathogenesis observed in KS.

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Activation of latent Kaposi's sarcoma-associated herpesvirus by demethylation of the promoter of the lytic transactivator

Cited by 142 publications

References 27 publications

C ^m C(A/T)GG DNA methylation in mature B cell lymphoma gene silencing

C ^m C(A/T)GG DNA methylation in mature B cell lymphoma gene silencing

Viral epigenomes in human tumorigenesis

The role of Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8 regulator of transcription activation (RTA) in control of gene expression

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Activation of latent Kaposi's sarcoma-associated herpesvirus by demethylation of the promoter of the lytic transactivator

Cited by 142 publications

References 27 publications

C m C(A/T)GG DNA methylation in mature B cell lymphoma gene silencing

C m C(A/T)GG DNA methylation in mature B cell lymphoma gene silencing

Viral epigenomes in human tumorigenesis

The role of Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8 regulator of transcription activation (RTA) in control of gene expression

Contact Info

Product

Resources

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C ^m C(A/T)GG DNA methylation in mature B cell lymphoma gene silencing

C ^m C(A/T)GG DNA methylation in mature B cell lymphoma gene silencing