Sequence-Specific Methylation Inhibits the Activity of the Epstein-Barr Virus LMP 1 and BCR2 Enhancer-Promoter Regions

Minárovits, János; Hu, Li–Fu; Minarovits-Kormuta, S.; Klein, George; Ernberg, Ingemar

doi:10.1006/viro.1994.1229

Cited by 45 publications

(39 citation statements)

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“…This discrepancy may be due to the different passage history of the cells used. While Cp activity is regulated by both CpG methylation (Altiok et al, 1992;Minarovits et al, 1994;Robertson et al, 1995;Salamon et al, 2001;Bakos et al, 2007) and histone modifications (this study), Qp is unmethylated independently of its activity (Tao et al, 1998;Salamon et al, 2001). We observed that similar to active Cp, active Q promoters in lymphoid and epithelial cells are also located on an acetylation island enriched in AcH3 and AcH4.…”

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confidence: 57%

Latency type-specific distribution of epigenetic marks at the alternative promoters Cp and Qp of Epstein–Barr virus

Fejér

Koroknai

Bánáti

et al. 2008

Journal of General Virology

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Transcripts for the Epstein-Barr virus (EBV)-encoded nuclear antigens are initiated at the alternative promoters Wp, Cp and Qp. Although the host cell-dependent activity of Cp is regulated by DNA methylation, Qp is unmethylated independently of its activity. Because histone modifications affect the chromatin structure, we compared the levels of diacetylated histone H3, tetraacetylated histone H4 and histone H3 dimethylated on lysine 4 (H3K4me2) at Cp and Qp, in well characterized cell lines representing the major EBV latency types. We found an activity-dependent histone code: acetylated histones marked active Cp, whereas active Qp was selectively enriched both in acetylated histones and H3K4me2. We concluded that active (but not silent) Cp and Qp are located to 'acetylation islands' in latent, episomal EBV genomes, similar to the active chromatin domains of the human genome.

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confidence: 57%

Latency type-specific distribution of epigenetic marks at the alternative promoters Cp and Qp of Epstein–Barr virus

Fejér

Koroknai

Bánáti

et al. 2008

Journal of General Virology

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“…Epigenetic events, like DNA methylation and histone modifications, constitute another level of regulatory mechanisms for EBNA2 and LMP1 expression (3,15,16,34,39,40,51,68,70). DNA methylation of proximal promoter elements correlates with the transcription repression of EBNA2 and LMP1 transcription in type I latency (3,16,58,66).…”

Section: -Azacytidine An Inhibitor Of Dna Methylation That Derepresmentioning

confidence: 99%

“…EBNA2 stimulates the Cp and LMP1 promoters through a cellular DNA binding protein called CSL (CBF1 or RBP-Jk) (20,22,35,77). CSL can also interact with cellular coactivators, like intracellular Notch, and corepressors, like CIR, that may regulate EBV latency transcripts in the absence of EBNA2 (11,23,24,77).Epigenetic events, like DNA methylation and histone modifications, constitute another level of regulatory mechanisms for EBNA2 and LMP1 expression (3,15,16,34,39,40,51,68,70). DNA methylation of proximal promoter elements correlates with the transcription repression of EBNA2 and LMP1 transcription in type I latency (3,16,58,66).…”

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confidence: 99%

Dynamic Chromatin Boundaries Delineate a Latency Control Region of Epstein-Barr Virus

Chau

Lieberman

2004

J Virol

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. We have used the chromatin immunoprecipitation assay to examine the chromatin architecture of the LCR in different types of EBV latency programs. We have found that histone H3 K4 methylation (H3mK4) was enriched throughout a large domain that extended from internal repeat 1 (IR1) to the terminal repeat in type III latency where EBNA2 and LMP1 genes are expressed. In type I latency where EBNA2 and LMP1 genes are transcriptionally silent, the H3mK4 domain contracts and does not enter the EBNA2 or LMP1 promoters. In contrast, histone H3 K9 methylation (H3mK9), associated with silent heterochromatin, was enriched in the EBNA2 EBNA2 and LMP1 are essential for EBV-induced cellular proliferation and immortalization of primary B lymphocytes (9, 25). However, their expression can be down-regulated during latency. At least four different gene expression patterns have been characterized for various forms of EBV latency found in different tumors or host cell types (5, 6, 53). For example, EBV immortalized lymphoblastoid cell lines (LCLs) express the full panoply of viral oncogenes in a transcription program referred to as type III latency (54). In contrast, viral latency in healthy donors or in most BL-derived cell lines expresses a more restricted transcription program referred to as type I, where EBNA2 and LMP1 transcription are repressed. EBNA2 is a transcriptional regulatory protein that binds to the LMP1 and EBNA2 promoters and enforces the type III latency program (1,17,20,22,71,78). The regulation of EBNA2 expression is, therefore, critical in determining the latency program and the proliferative capacity of EBV-infected cells.The transcriptional control of EBNA2 is complex (22,41,42,69,70,75,76). During the establishment of EBV latency, EBNA2 transcription initiates at a promoter in internal repeat 1 (IR1) referred to as Wp. Once EBNA2 protein levels reach a threshold, the protein activates a second promoter upstream of Wp, referred to as Cp. EBNA2 stimulates the Cp and LMP1 promoters through a cellular DNA binding protein called CSL (CBF1 or RBP-Jk) (20,22,35,77). CSL can also interact with cellular coactivators, like intracellular Notch, and corepressors, like CIR, that may regulate EBV latency transcripts in the absence of EBNA2 (11,23,24,77).Epigenetic events, like DNA methylation and histone modifications, constitute another level of regulatory mechanisms for EBNA2 and LMP1 expression (3,15,16,34,39,40,51,68,70). DNA methylation of proximal promoter elements correlates with the transcription repression of EBNA2 and LMP1 transcription in type I latency (3,16,58,66). Inhibitors of DNA methylation relieve this repression and induce a switch from type I to type III latency patterns of EBV gene expression (3,26). Histone modifications are also known to be important for EBNA2 regulation since transcription activation correlates with promoter-specific histone hyperacetylation and histone acetyltransferase association (2, 72). Moreover, the CSL corepressors CIR and EBNA3A/C are known to associate with

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“…A number of studies have shown that the type III latency EBNA gene promoters, Cp and Wp, are inactivated by CpG methylation during type I latency (2,10,22,44,49,62,69), while Qp is at the center of a hypomethylated island and remains active (73). Although evidence strongly suggests that methylation of Cp and Wp is absolutely required for EBV to stably maintain the type I and II latency programs (73), almost nothing is known about the specific trans-acting factors which regulate transcription from Qp.…”

Section: Epstein-barr Virus (Ebv) Infection In Immunocompetentmentioning

confidence: 99%

Constitutive Activation of Epstein-Barr Virus (EBV) Nuclear Antigen 1 Gene Transcription by IRF1 and IRF2 during Restricted EBV Latency

Schaefer

Paulson

Strominger

et al. 1997

Molecular and Cellular Biology

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Epstein-Barr virus (EBV) infection in immunocompetenthumans is predominantly latent and persists for the life of the individual (reviewed in reference 41). Recently, it has been shown that EBV is capable of adopting at least three distinct forms of latency (27). Type III latency is observed upon in vitro infection of B lymphocytes and results in immortalization and continuous proliferation of the infected B cells via the action of a subset of the six EBV nuclear antigens (EBNAs; EBNA1, EBNA2, EBNA3a, EBNA3b, EBNA3c, and EBNA4) and three membrane proteins (LMP1, LMP2a, and LMP2b) expressed in the type III (immortalizing) program. However, in vivo, the type III latency program is likely to be only transiently observed upon initial infection of a naive host, since several of the type III latent antigens elicit a potent cytotoxic T-lymphocyte response resulting in very effective elimination of type III latently infected B cells (reviewed in reference 33).EBV is also capable of entering programs of latency in which the expression of latent antigens is restricted with respect to the type III program. In type I latency, only the EBNA1 protein is expressed (64). It has recently been shown that EBNA1 peptides do not enter the major histocompatibility complex class I antigen processing and presentation pathway (29, 39, 52), and cells which express only EBNA1 are not detected by host cellular immune surveillance mechanisms (63). The type II latency program differs from type I latency only in the expression of variable combinations of LMP1, LMP2a, and LMP2b, in addition to EBNA1. Since the type I latency program was identified, there has been speculation that type I latently infected B lymphocytes represent the lifelong reservoir of virus in immunocompetent, seropositive individuals, and there have recently been several reports which provide evidence that a type I-like form of restricted viral latency does indeed exist in healthy carriers of EBV (6,51,60,85).Investigations into the molecular basis of type III and type I latency have demonstrated that distinct promoters are used to drive transcription of the EBNAs in each latent program. In type III latency, transcription of all six nuclear antigens is initiated from either Wp (during initial infection of resting B cells) or Cp (in cycling B cells), and the long primary transcripts are differentially spliced to generate the mature EBNA transcripts (75, 94; see Fig. 1A for a schematic representation of EBV latent transcription and locations of promoters). Recent investigations have shown that transcription of the EBNA1 gene in type I latency is driven by a promoter designated Qp, which is considerably downstream of the type III latency EBNA gene promoters (57,(70)(71)(72). Qp has an architecture with numerous similarities to eukaryotic housekeeping

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Sequence-Specific Methylation Inhibits the Activity of the Epstein-Barr Virus LMP 1 and BCR2 Enhancer-Promoter Regions

Cited by 45 publications

References 0 publications

Latency type-specific distribution of epigenetic marks at the alternative promoters Cp and Qp of Epstein–Barr virus

Latency type-specific distribution of epigenetic marks at the alternative promoters Cp and Qp of Epstein–Barr virus

Dynamic Chromatin Boundaries Delineate a Latency Control Region of Epstein-Barr Virus

Constitutive Activation of Epstein-Barr Virus (EBV) Nuclear Antigen 1 Gene Transcription by IRF1 and IRF2 during Restricted EBV Latency

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