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

Overview of attention for article published in Journal of Virology, July 2016
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Title
Epstein-Barr Virus Oncoprotein LMP1 Mediates Epigenetic Changes in Host Gene Expression through PARP1
Published in
Journal of Virology, July 2016
DOI 10.1128/jvi.01180-16
Pubmed ID
Authors

Kayla A. Martin, Lena N. Lupey, Italo Tempera

Abstract

The latent infection of Epstein-Barr virus (EBV) is associated with 1% of human cancer incidence. Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification catalyzed by poly(ADP-ribose) polymerases (PARPs) that mediates 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 compared to EBV-negative B cells. Moreover, cellular PAR levels were up to two-fold greater in Type III compared to 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. Epstein-Barr virus (EBV) 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.

Twitter Demographics

The data shown below were collected from the profile of 1 tweeter who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 25 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 25 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 5 20%
Student > Master 5 20%
Student > Bachelor 4 16%
Researcher 3 12%
Student > Doctoral Student 1 4%
Other 2 8%
Unknown 5 20%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 9 36%
Agricultural and Biological Sciences 6 24%
Immunology and Microbiology 3 12%
Medicine and Dentistry 1 4%
Neuroscience 1 4%
Other 0 0%
Unknown 5 20%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 22 July 2016.
All research outputs
#10,982,396
of 12,359,087 outputs
Outputs from Journal of Virology
#12,127
of 13,153 outputs
Outputs of similar age
#219,984
of 263,875 outputs
Outputs of similar age from Journal of Virology
#202
of 227 outputs
Altmetric has tracked 12,359,087 research outputs across all sources so far. This one is in the 1st percentile – i.e., 1% of other outputs scored the same or lower than it.
So far Altmetric has tracked 13,153 research outputs from this source. They receive a mean Attention Score of 4.9. This one is in the 1st percentile – i.e., 1% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 263,875 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 1st percentile – i.e., 1% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 227 others from the same source and published within six weeks on either side of this one. This one is in the 1st percentile – i.e., 1% of its contemporaries scored the same or lower than it.