The transcriptional repressor NIPP1 is an essential player in EZH2-mediated gene silencing

Nuytten, Mieke; Beke, Lijs; Eynde, Aleyde Van; Ceulemans, Hugo; Beullens, Monique; Hummelen, Paul Van; Fuks, François; Bollen, Mathieu

doi:10.1038/sj.onc.1210774

Cited by 71 publications

(91 citation statements)

References 48 publications

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“…Although EZH2 is commonly known for its role in gene silencing through generation of H3K27me3, several works reveal that EZH2 also positively regulates gene expression through both indirect effects and effects that are independent of its catalytic activity (33)(34)(35). Our study also identified a subset of olaparib-affected genes of LCL cells that are included in the group of targets positively regulated by EZH2 in PC3 cells, supporting the additional role for EZH2 itself as a positive regulator of gene expression.…”

Section: Discussionsupporting

confidence: 49%

“…GSEA identified olaparib-affected genes enriched in the EZH2 target gene data set. In the work by Nuytten et al, depletion of EZH2 resulted in both activation and repression of a subset of genes (35). Thus, in cells depleted of EZH2, genes that were upregulated represent genes for which EZH2 acts as a repressor, while genes that were downregulated represent genes for which EZH2 functions, likely indirectly, as a transcriptional activator.…”

Section: Lcl Cells Tolerate Parp Inhibitionmentioning

confidence: 99%

“…We performed gene set enrichment analysis (GSEA) of the genes in the ranked list of genes significantly affected by olaparib by at least 1.3-fold (q Ͻ 0.01) at 72 h compared to a publicly available, predefined subset of EZH2 target genes. As no data sets for EZH2 targets in LCL cells were available, we used two data sets comprised of genes affected by EZH2 knockdown in the prostate cancer epithelial cell line PC3 (35). GSEA identified olaparib-affected genes enriched in the EZH2 target gene data set.…”

Section: Lcl Cells Tolerate Parp Inhibitionmentioning

confidence: 99%

See 2 more Smart Citations

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

Martin

Cesaroni

Denny

et al. 2015

Molecular and Cellular Biology

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Section: Discussionsupporting

confidence: 49%

Section: Lcl Cells Tolerate Parp Inhibitionmentioning

confidence: 99%

Section: Lcl Cells Tolerate Parp Inhibitionmentioning

confidence: 99%

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

Martin

Cesaroni

Denny

et al. 2015

Molecular and Cellular Biology

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“…involved in gene silencing, at least in part through trimethylating histone 3 Lys 27. It also interacts with DNA methyltransferases and it is necessary for the methylation of target DNA (Vire et al, 2006;Nuytten et al, 2008). Through these interactions, the downregulation of the gene coding for Ser/Thr protein phosphatase in the F 1 Zn þ and F 1 Zn À daphnids could be a reason for their reduced global DNA methylation.…”

Section: Discussionmentioning

confidence: 99%

Gene transcription profiles, global DNA methylation and potential transgenerational epigenetic effects related to Zn exposure history in Daphnia magna

Vandegehuchte

Coninck

Vandenbrouck

et al. 2010

Environmental Pollution

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Zn-induced DNA hypomethylation is related to gene transcription in Daphnia magna and Zn exposure potentially induced limited temporary transgenerational effects on gene transcription. a r t i c l e i n f o a b s t r a c tA reduced level of DNA methylation has recently been described in both Zn-exposed and non-exposed offspring of Daphnia magna exposed to Zn. The hypothesis examined in this study is that DNA hypomethylation has an effect on gene transcription. A second hypothesis is that accumulative epigenetic effects can affect gene transcription in non-exposed offspring from parents with an exposure history of more than one generation. Transcriptional gene regulation was studied with a cDNA microarray. In the exposed and non-exposed hypomethylated daphnids, a large proportion of common genes were similarly up-or down-regulated, indicating a possible effect of the DNA hypomethylation. Two of these genes can be mechanistically involved in DNA methylation reduction. The similar transcriptional regulation of two and three genes in the F 0 and F 1 exposed daphnids on one hand and their non-exposed offspring on the other hand, could be the result of a one-generation temporary transgenerational epigenetic effect, which was not accumulative.

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“…Our work extends these previous findings by providing a mechanism demonstrating that LMP1, through PARP1, affects EZH2 and H3K27me3. Since EZH2 also promotes gene expression by mechanisms that are independent of its catalytic activity (50,51), EBV may exploit multiple regulatory functions of EZH2, some of which directly alter host transcription without associated epigenetic modifications. Therefore, this work defines a mechanism for LMP1-mediated host gene expression regulation via PARP1-dependent inhibition of H3K27me3 production and possibly suppression of EZH2 transactivation.…”

Section: Discussionmentioning

confidence: 99%

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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The transcriptional repressor NIPP1 is an essential player in EZH2-mediated gene silencing

Cited by 71 publications

References 48 publications

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

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

Gene transcription profiles, global DNA methylation and potential transgenerational epigenetic effects related to Zn exposure history in Daphnia magna

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

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