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Journal of Virology, June 2007, p. 5929-5939, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02606-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Suppression of Viral Gene Expression in Bovine Leukemia Virus-Associated B-Cell Malignancy: Interplay of Epigenetic Modifications Leading to Chromatin with a Repressive Histone Code{triangledown}

Makram Merimi,1 Pavel Klener,1,2 Maud Szynal,1 Yvette Cleuter,1 Pierre Kerkhofs,3 Arsène Burny,1 Philippe Martiat,1 and Anne Van den Broeke1*

Laboratory of Experimental Hematology, Bordet Institute, 1000 Brussels, Belgium,1 Institute of Pathological Physiology, Charles University, Prague, Czech Republic,2 Veterinary and Agrochemical Research Centre (CERVA-CODA), 1180 Uccle, Belgium3

Received 25 November 2006/ Accepted 12 March 2007

Ovine leukemia/lymphoma resulting from bovine leukemia virus infection of sheep offers a large animal model for studying mechanisms underlying leukemogenesis. Silencing of viral information including Tax, the major contributor to the oncogenic potential of the virus, is critical if not mandatory for tumor progression. In this study, we have identified epigenetic mechanisms that govern the complete suppression of viral expression, using a lymphoma-derived B-cell clone carrying a silent provirus. Silencing was not relieved by injection of the malignant B cells into sheep. However, exogenous expression of Tax or treatment with either the DNA methyltransferase inhibitor 5'azacytidine or the histone deacetylase (HDAC) inhibitor trichostatin A rescued viral expression, as demonstrated by in vivo infectivity trials. Comparing silent and reactivated provirus, we found mechanistic connections between chromatin conformation and tumor-associated transcriptional repression. Silencing is associated with DNA methylation and decreased accessibility of promoter sequences. HDAC1 and the transcriptional corepressor mSin3A are associated with the inactive but not the reactivated promoter. Silencing correlates with a repressed chromatin structure marked by histone H3 and H4 hypoacetylation, a loss of methylation at H3 lysine 4, and an increase of H3 lysine 9 methylation. These observations point to the critical role of epigenetic mechanisms in tumor-specific virus/oncogene silencing, a potential strategy to evade immune response and favor the propagation of the transformed cell.

* Corresponding author. Mailing address: Laboratory of Experimental Hematology, Bordet Institute, ULB, 121, Blvd. de Waterloo, 1000 Brussels, Belgium. Phone: (32) 2 541 37 40. Fax: (32) 2 541 34 53. E-mail: anne.vandenbroeke{at}bordet.be

{triangledown} Published ahead of print on 28 March 2007.

Journal of Virology, June 2007, p. 5929-5939, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02606-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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