This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Calomme, C. Articles by Van Lint, C. Search for Related Content PubMed PubMed Citation Articles by Calomme, C. Articles by Van Lint, C.

Overlapping CRE and E Box Motifs in the Enhancer Sequences of the Bovine Leukemia Virus 5' Long Terminal Repeat Are Critical for Basal and Acetylation-Dependent Transcriptional Activity of the Viral Promoter: Implications for Viral Latency

Laboratoire de Virologie Moléculaire, Service de Chimie Biologique, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, Gosselies,¹ Laboratoire d'Hématologie Expérimentale, Institut J. Bordet, Université Libre de Bruxelles, Brussels,² Unité de Biologie Cellulaire et Moléculaire, Faculté Universitaire des Sciences Agronomiques de Gembloux, Gembloux, Belgium³

Received 28 May 2004/ Accepted 4 August 2004

Bovine leukemia virus (BLV) infection is characterized by viral latency in a large proportion of cells containing an integrated provirus. In this study, we postulated that mechanisms directing the recruitment of deacetylases to the BLV 5' long terminal repeat (LTR) could explain the transcriptional repression of viral expression in vivo. Accordingly, we showed that BLV promoter activity was induced by several deacetylase inhibitors (such as trichostatin A [TSA]) in the context of episomal LTR constructs and in the context of an integrated BLV provirus. Moreover, treatment of BLV-infected cells with TSA increased H4 acetylation at the viral promoter, showing a close correlation between the level of histone acetylation and transcriptional activation of the BLV LTR. Among the known cis-regulatory DNA elements located in the 5' LTR, three E box motifs overlapping cyclic AMP responsive elements (CREs) in U3 were shown to be involved in transcriptional repression of BLV basal gene expression. Importantly, the combined mutations of these three E box motifs markedly reduced the inducibility of the BLV promoter by TSA. E boxes are susceptible to recognition by transcriptional repressors such as Max-Mad-mSin3 complexes that repress transcription by recruiting deacetylases. However, our in vitro binding studies failed to reveal the presence of Mad-Max proteins in the BLV LTR E box-specific complexes. Remarkably, TSA increased the occupancy of the CREs by CREB/ATF. Therefore, we postulated that the E box-specific complexes exerted their negative cooperative effect on BLV transcription by steric hindrance with the activators CREB/ATF and/or their transcriptional coactivators possessing acetyltransferase activities. Our results thus suggest that the overlapping CRE and E box elements in the BLV LTR were selected during evolution as a novel strategy for BLV to allow better silencing of viral transcription and to escape from the host immune response.

This article has been cited by other articles:

• Jiang, X., Tian, F., Du, Y., Copeland, N. G., Jenkins, N. A., Tessarollo, L., Wu, X., Pan, H., Hu, X.-Z., Xu, K., Kenney, H., Egan, S. E., Turley, H., Harris, A. L., Marini, A. M., Lipsky, R. H. (2008). BHLHB2 Controls Bdnf Promoter 4 Activity and Neuronal Excitability. J. Neurosci. 28: 1118-1130 [Abstract] [Full Text]  
• Nguyen, T. L.-A., de Walque, S., Veithen, E., Dekoninck, A., Martinelli, V., de Launoit, Y., Burny, A., Harrod, R., Van Lint, C. (2007). Transcriptional Regulation of the Bovine Leukemia Virus Promoter by the Cyclic AMP-response Element Modulator {tau} Isoform. J. Biol. Chem. 282: 20854-20867 [Abstract] [Full Text]  
• Merimi, M., Klener, P., Szynal, M., Cleuter, Y., Kerkhofs, P., Burny, A., Martiat, P., Van den Broeke, A. (2007). 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. J. Virol. 81: 5929-5939 [Abstract] [Full Text]  
• Esumi, N., Kachi, S., Campochiaro, P. A., Zack, D. J. (2007). VMD2 Promoter Requires Two Proximal E-box Sites for Its Activity in Vivo and Is Regulated by the MITF-TFE Family. J. Biol. Chem. 282: 1838-1850 [Abstract] [Full Text]