Transcription Factor Binding and Histone Modifications on the Integrated Proviral Promoter in Human T-cell Leukemia Virus-I-infected T-cells

Abstract

The human T-cell leukemia virus (HTLV-I)-encodedTax protein is a potent transcriptional activator that stimulates expression of the integrated provirus. Biochemical studies indicate that Tax, together with cellular transcription factors, interacts with viral cAMP-response element enhancer elements to recruit the pleiotropic coactivators CREB-binding protein and p300. Histone acetylation by these coactivators has been shown to play a major role in activating HTLV-I transcription from chromatin templates in vitro. However, the extent of histone modification and the precise identity of the cellular regulatory proteins bound at the HTLV-I promoter in vivo is not known. Chromatin immunoprecipitation analysis was used to investigate factor binding and histone modification at the integrated HTLV-I provirus in infected T-cells (SLB-1). These studies reveal the presence of Tax, a variety of ATF/CREB and AP-1 family members (CREB, CREB-2, ATF-1, ATF-2, c-Fos, and c-Jun), and both p300 and CREB-binding protein at the HTLV-I promoter. Consistent with the binding of these coactivators, we observed histone H3 and H4 acetylation at three regions within the proviral genome. Histone deacetylases were also present at the viral promoter and, following their inhibition, we observe an increase in histone H4 acetylation on the HTLV-I promoter and a concomitant increase in viral RNA. Together, these results suggest that a variety of transcriptional activators, coactivators, and histone deacetylases participate in the regulation of HTLV-I transcription in infected T-cells.

The HBZ Factor of Human T-cell Leukemia Virus Type I Dimerizes with Transcription Factors JunB and c-Jun and Modulates Their Transcriptional Activity

“…expression of the HTLV-I promoter (42,43), with the viral CRE sites being the functional c-Jun-responsive targets in the promoter (42). In light of our results, HBZ should be able to down-regulate viral transcription in the presence of c-Jun.…”

“…Then, the promoter-bound Tax molecule recruits the transcriptional coactivator CREB-binding protein, which is involved in the acetylation of the core histone tails (40,41). AP-1 is also able to transactivate the HTLV-I promoter in vivo (42,43). However, no direct interactions between the AP-1 factors and Tax have been characterized, suggesting that AP-1 is obviously involved in basal transcription of the HTLV-I genome.…”

Tax-dependent Displacement of Nucleosomes during Transcriptional Activation of Human T-Cell Leukemia Virus Type 1

“…Among proteins that carry intrinsic histone acetyltransferase activity, the coactivators CBP/p300 have been shown to have an essential role in HTLV-1 transcriptional activation. Our laboratories, as well as others, detected CBP/p300 at the integrated HTLV-1 promoter in T-cells expressing high levels of Tax (23,24). This finding is consistent with several previous studies showing that Tax directly facilitates the recruitment of CBP/p300 to the HTLV-1 promoter (16,17,25,26).…”

“…Using chromatin assembled with core histones lacking their amino-terminal tails and using specific inhibitors of CBP/p300, we have found that CBP/p300 participate in critical chromatin-specific, histone tail-independent acetylation events during transcriptional activation by Tax (28). These data suggest that, in addition to the core histone tails, another target of acetylation by p300 functions in mediating strong Tax transactivation in a chromatin environment.In previous studies we have examined transcription factor binding and histone modifications at the viral promoter in Tax-expressing, HTLV-1-infected cells (23,29). In this study, we sought to better define the epigenetic changes that occur during Tax-dependent activation of HTLV-1 LTR-directed transcription in vivo.…”

“…Additionally, this and other histone modifications can serve as a platform for the binding of transcriptional regulatory proteins (22). Previous studies have demonstrated that histone deacetylase inhibitors increase the level of HTLV-1 transcription and that Tax and histone deacetylase complex occupancy are mutually exclusive (23,24). It has also been shown that an increase in histone tail acetylation on HTLV-1 promoter-associated nucleosomes correlates with an increase in viral RNA in HTLV-1-infected T-cells.…”