Global Transcriptome Analysis Reveals That Poly(ADP-Ribose) Polymerase 1 Regulates Gene Expression through EZH2

Martin, Kayla; Cesaroni, Matteo; Denny, Michael F.; Lupey, Lena N.; Tempera, Italo

doi:10.1128/mcb.00635-15

Cited by 35 publications

(40 citation statements)

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“…We have previously shown that PARP1 activity regulates the expression and function of EZH2, preventing gene silencing mediated by the repressive histone mark H3K27me3 (18). In this study, we report for the first time the induction of two tumorpromoting genes, c-Fos and EGR1 (45,46), as key targets of LMP1 through the PARP1/EZH2 axis.…”

Section: Discussionmentioning

confidence: 59%

“…Our recent work indicates that PARP1 regulates B cell receptor stimulation and the immune response (18). This link between PARP activity and B cell function is supported by the observation that transcription factors that participate in the immune response, such as interleukin-2 (IL-2) and gamma interferon (IFN-␥), likely contribute to PARP-mediated gene regulation (18,54).…”

Section: Discussionmentioning

confidence: 84%

“…The activation of PARP1 by LMP1 may have important consequences for the expression of host genes and associated cell functions. PARP1 regulates global gene expression by altering chromatin (37,38), and we recently reported a reciprocal relationship between PARP1 activity and the expression and function of EZH2 (18). EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that mediates trimethylation of lysine 27 of histone H3 (H3K27me3), a repressive histone mark that is associated with gene silencing (39).…”

Section: Ectopic Expression Of Lmp1 In Mef Parp1mentioning

confidence: 99%

“…EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that mediates trimethylation of lysine 27 of histone H3 (H3K27me3), a repressive histone mark that is associated with gene silencing (39). PARP1 activity suppresses the expression of EZH2, which blocks accumulation of H3K27me3 at EZH2 target genes and prevents gene silencing (18). Thus, the activation of PARP1 by LMP1 should decrease global H3K27me3 levels in type III compared to type I cells.…”

Section: Ectopic Expression Of Lmp1 In Mef Parp1mentioning

confidence: 99%

“…PARylation of histones reduces their affinity for DNA due to electrostatic repulsion (13), creating a more relaxed, or decondensed, chromatin structure which makes the DNA more accessible to DNA repair or transcriptional machineries (13)(14)(15). Additionally, the PARP1 protein plays an important regulatory role in gene expression, mainly promoting transcriptional activation through epigenetic mechanisms (13,(16)(17)(18). The host also uses PARylation, specifically through the PARP1 protein, to regulate both the lytic and latent infection of EBV (19,20).…”

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confidence: 99%

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Epstein-Barr Virus Oncoprotein LMP1 Mediates Epigenetic Changes in Host Gene Expression through PARP1

Martin

Lupey

Tempera

2016

J Virol

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The latent infection of Epstein-Barr virus (EBV) is associated with 1% of human cancer incidence. Poly(ADP-ribosyl)ation (PARylation) is a posttranslational modification catalyzed by poly(ADP-ribose) polymerases (PARPs) that mediate EBV replication during latency. In this study, we detail the mechanisms that drive cellular PARylation during latent EBV infection and the effects of PARylation on host gene expression and cellular function. EBV-infected B cells had higher PAR levels than EBV-negative B cells. Moreover, cellular PAR levels were up to 2-fold greater in type III than type I latently infected EBV B cells. We identified a positive association between expression of the EBV genome-encoded latency membrane protein 1 (LMP1) and PAR levels that was dependent upon PARP1. PARP1 regulates gene expression by numerous mechanisms, including modifying chromatin structure and altering the function of chromatin-modifying enzymes. Since LMP1 is essential in establishing EBV latency and promoting tumorigenesis, we explored the model that disruption in cellular PARylation, driven by LMP1 expression, subsequently promotes epigenetic alterations to elicit changes in host gene expression. PARP1 inhibition resulted in the accumulation of the repressive histone mark H3K27me3 at a subset of LMP1-regulated genes. Inhibition of PARP1, or abrogation of PARP1 expression, also suppressed the expression of LMP1-activated genes and LMP1-mediated cellular transformation, demonstrating an essential role for PARP1 activity in LMP1-induced gene expression and cellular transformation associated with LMP1. In summary, we identified a novel mechanism by which LMP1 drives expression of host tumor-promoting genes by blocking generation of the inhibitory histone modification H3K27me3 through PARP1 activation. IMPORTANCEEBV is causally linked to several malignancies and is responsible for 1% of cancer incidence worldwide. The EBV-encoded protein LMP1 is essential for promoting viral tumorigenesis by aberrant activation of several well-known intracellular signaling pathways. We have identified and defined an additional novel molecular mechanism by which LMP1 regulates the expression of tumor-promoting host genes. We found that LMP1 activates the cellular protein PARP1, leading to a decrease in a repressive histone modification, accompanied by induction in expression of multiple cancer-related genes. PARP1 inhibition or depletion led to a decrease in LMP1-induced cellular transformation. Therefore, targeting PARP1 activity may be an effective treatment for EBV-associated malignancies. The Epstein-Barr virus (EBV) is a human gammaherpesvirus that latently infects approximately 95% of the population worldwide (1). Latent EBV infection contributes to 1% of human cancers, including Burkitt's lymphoma and nasopharyngeal carcinoma (2, 3). To establish a latent infection in a naive B cell, EBV first adopts a type III latent gene expression program in which all latency genes are expressed to provide intracellular signals to the infected B cell th...

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Section: Discussionmentioning

confidence: 59%