Inhibition of histone deacetylases induces bovine leukemia virus expression in vitro and in vivo.
Packaging into nucleosomes results in a global transcriptional repression as a consequence of exclusion of sequence-specific factors. This inhibition can be relieved by using inhibitors of histone deacetylases, acetylation being a major characteristic of transcriptionally active chromatin. Paradoxically, the expression of only approximately 2% of the total cellular genes is modulated by histone hyperacetylation. To unravel the potential role of this transcriptional control on BLV expression, we tested the effect of two highly specific inhibitors of deacetylases, trichostatin A (TSA) and trapoxin (TPX). Our results demonstrate that treatment with TSA efficiently enhanced long terminal repeat-directed gene expression of integrated reporter constructs in heterologous D17 stable cell lines. To further examine the biological relevance of these observations made in vitro, we analyzed ex vivo-isolated peripheral blood mononuclear cells (PBMCs) from bovine leukemia virus (BLV)-infected sheep. TSA deacetylase inhibitor induced a drastic increase in viral expression at levels comparable to those induced by treatment with phorbol-12-myristate 13-acetate and ionomycin, the most efficient activators of BLV expression known to date. TSA acted directly on BLV-infected B lymphocytes to increase viral expression and does not seem to require T-cell cooperation. Inhibition of deacetylation after treatment with TSA or TPX also significantly increased viral expression in PBMCs from cattle, the natural host for BLV. Together, our results show that BLV gene expression is, like that of a very small fraction of cellular genes, also regulated by deacetylation.
Merezak
C
C
Molecular and Cellular Biology, Faculty of Agronomy, Gembloux, Belgium.
Reichert
M
M
Van Lint
C
C
Kerkhofs
P
P
Portetelle
D
D
Willems
L
L
Kettmann
R
R
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000821:virology; D002417:Cattle; D002460:Cell Line; D002478:Cells, Cultured; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015967:Gene Expression Regulation, Viral; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D001909:Leukemia Virus, Bovine / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D010455:Peptides; D010703:Phorbol Esters / Q000494:pharmacology; D012756:Sheep; D014158:Transcription, Genetic / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010455:Peptides; D010703:Phorbol Esters; C067070:trapoxin A; C012589:trichostatin A; D015759:Ionomycin; C032974:12-O-retinoylphorbol-13-acetate