Abstract
The human T-cell leukemia virus (HTLV-I)-encoded Tax 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.
Highlights
Human T-cell leukemia virus type-I (HTLV-I)1 is a complex retrovirus etiologically linked to an aggressive and often fatal malignancy called adult T-cell leukemia [1, 2]
In addition to Tax and CREB, a number of ATF/CREB and AP-1 family members associate with the HTLV-I transcriptional control region in vivo
Multiple Transcription Factors from the ATF/CREB and AP-1 Families Bind to the HTLV-I Promoter in Vivo—Several transcription factors from the ATF/CREB family are known to bind the viral CREs, and some of these have been shown to activate HTLV-I transcription in transient transfection assays
Summary
Human T-cell leukemia virus type-I (HTLV-I) is a complex retrovirus etiologically linked to an aggressive and often fatal malignancy called adult T-cell leukemia [1, 2]. Three conserved 21-base pair enhancer elements are critical to Tax-activated transcription (6 – 8) These elements, referred to as viral cyclic AMPresponse element (viral CREs), carry a central CRE that serves as a binding site for members of the ATF/CREB family of transcription factors. The molecular interactions between Tax and CREB are well established in vitro; whether CREB and/or other ATF/CREB family members participate in HTLV-I transcription in living cells is unknown Other proteins, such as CREB-2 (29 –32), ATF-1 [14, 15, 33], ATF-2 [15, 34], CREM [20, 33, 35], and the AP-1 proteins (36 –39), have been implicated in binding to the viral CREs and mediating HTLV-I gene expression. Treatment of HTLV-I-infected cells with the histone deacetylase inhibitors trichostatin A or sodium butyrate increases H4 acetylation at the HTLV-I promoter and enhances viral transcription, further supporting a direct role for histone acetylation in HTLV-I gene expression
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