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Inactivation of intergenic enhancers by EBNA3A initiates and maintains polycomb signatures across a chromatin domain encoding CXCL10 and CXCL9.
PLoS Pathog. 9:e1003638 (2013)
Epstein-Barr virus (EBV) causes a persistent infection in human B cells by establishing specific transcription programs to control B cell activation and differentiation. Transcriptional reprogramming of EBV infected B cells is predominantly driven by the action of EBV nuclear antigens, among them the transcriptional repressor EBNA3A. By comparing gene expression profiles of wt and EBNA3A negative EBV infected B cells, we have previously identified a broad array of cellular genes controlled by EBNA3A. We now find that genes repressed by EBNA3A in these cells are significantly enriched for the repressive histone mark H3K27me3, which is installed by Polycomb group (PcG) proteins. This PcG-controlled subset of genes also carries H3K27me3 marks in a variety of other tissues, suggesting that the commitment to PcG silencing is an intrinsic feature of these gene loci that can be used by EBNA3A. In addition, EBNA3A targets frequently reside in co-regulated gene clusters. To study the mechanism of gene repression by EBNA3A and to evaluate the relative contribution of PcG proteins during this process, we have selected the genomic neighbors CXCL10 and CXCL9 as a model for co-repressed and PcG-controlled genes. We show that EBNA3A binds to CBF1 occupied intergenic enhancers located between CXCL10 and CXCL9 and displaces the transactivator EBNA2. This impairs enhancer activity, resulting in a rapid transcriptional shut-down of both genes in a CBF1-dependent manner and initiation of a delayed gain of H3K27me3 marks covering an extended chromatin domain. H3K27me3 marks increase gradually and are maintained by EBNA3A. Our study provides direct evidence that repression by EBNA3A requires CBF1 and that EBNA3A and EBNA2 compete for access to CBF1 at identical genomic sites. Most importantly, our results demonstrate that transcriptional silencing by EBNA3A precedes the appearance of repressive PcG marks and indicate that both events are triggered by loss of enhancer activity.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Epstein-barr-virus ; Nuclear Antigen 3c ; Lymphoblastoid Cell-lines ; Rbp-j-kappa ; Gene-expression ; Group Proteins ; Human Genome ; Ink4b-arf-ink4a Locus ; Epigenetic Regulation ; Histone Modifications
Language
english
Publication Year
2013
HGF-reported in Year
2013
ISSN (print) / ISBN
1553-7366
e-ISSN
1553-7374
Journal
PLoS Pathogens
Quellenangaben
Volume: 9,
Issue: 9,
Article Number: e1003638
Publisher
Public Library of Science (PLoS)
Reviewing status
Peer reviewed
Institute(s)
Research Unit Gene Vector (AGV)
POF-Topic(s)
30203 - Molecular Targets and Therapies
Research field(s)
Immune Response and Infection
PSP Element(s)
G-501500-002
PubMed ID
24068939
WOS ID
WOS:000324922300047
Scopus ID
84884692313
Erfassungsdatum
2013-10-16