@article{Bazot:2015:10.1371/journal.ppat.1005031,
author = {Bazot, Q and Paschos, K and Skalska, L and Kalchschmidt, JS and Parker, GA and Allday, MJ},
doi = {10.1371/journal.ppat.1005031},
journal = {PLOS Pathogens},
title = {Epstein-Barr virus proteins EBNA3A and EBNA3C together induce expression of the oncogenic microRNA cluster miR-221/miR-222 and ablate expression of its target p57KIP2.},
url = {http://dx.doi.org/10.1371/journal.ppat.1005031},
volume = {11},
year = {2015}
}

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TY  - JOUR
AB  - We show that two host-encoded primary RNAs (pri-miRs) and the corresponding microRNA (miR) clusters - widely reported to have cell transformation-associated activity - are regulated by EBNA3A and EBNA3C. Utilising a variety of EBV-transformed lymphoblastoid cell lines (LCLs) carrying knockout-, revertant- or conditional-EBV recombinants, it was possible to demonstrate unambiguously that EBNA3A and EBNA3C are both required for transactivation of the oncogenic miR-221/miR-222 cluster that is expressed at high levels in multiple human tumours - including lymphoma/leukemia. ChIP, ChIP-seq, and chromosome conformation capture analyses indicate that this activation results from direct targeting of both EBV proteins to chromatin at the miR-221/miR-222 genomic locus and activation via a long-range interaction between enhancer elements and the transcription start site of a long non-coding pri-miR located 28kb upstream of the miR sequences. Reduced levels of miR-221/miR-222 produced by inactivation or deletion of EBNA3A or EBNA3C resulted in increased expression of the cyclin-dependent kinase inhibitor p57KIP2, a well-established target of miR-221/miR-222. MiR blocking experiments confirmed that miR-221/miR-222 target p57KIP2 expression in LCLs. In contrast, EBNA3A and EBNA3C are necessary to silence the tumour suppressor cluster miR-143/miR-145, but here ChIP-seq suggests that repression is probably indirect. This miR cluster is frequently down-regulated or deleted in human cancer, however, the targets in B cells are unknown. Together these data indicate that EBNA3A and EBNA3C contribute to B cell transformation by inhibiting multiple tumour suppressor proteins, not only by direct repression of protein-encoding genes, but also by the manipulation of host long non-coding pri-miRs and miRs.
AU  - Bazot,Q
AU  - Paschos,K
AU  - Skalska,L
AU  - Kalchschmidt,JS
AU  - Parker,GA
AU  - Allday,MJ
DO  - 10.1371/journal.ppat.1005031
PY  - 2015///
SN  - 1553-7366
TI  - Epstein-Barr virus proteins EBNA3A and EBNA3C together induce expression of the oncogenic microRNA cluster miR-221/miR-222 and ablate expression of its target p57KIP2.
T2  - PLOS Pathogens
UR  - http://dx.doi.org/10.1371/journal.ppat.1005031
UR  - http://www.ncbi.nlm.nih.gov/pubmed/26153983
UR  - http://hdl.handle.net/10044/1/25544
VL  - 11
ER  - 

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