Abstract
The human T-cell leukemia virus type 1 (HTLV-1) is integrated into the host cell DNA and assembled into nucleosomes. Within the repressive chromatin environment, the virally encoded Tax protein mediates the recruitment of the coactivators CREB-binding protein/p300 to the HTLV-1 promoter, located within the long terminal repeats (LTRs) of the provirus. These proteins carry acetyltransferase activity that is essential for strong transcriptional activation of the virus in the context of chromatin. Consistent with this, the amino-terminal tails of nucleosomal histones at the viral promoter are acetylated in Tax-expressing cells. We have developed a system in which we transfect Tax into cells carrying integrated copies of the HTLV-1 LTR driving the luciferase gene to analyze changes in "activating" histone modifications at the LTR. Unexpectedly, Tax transactivation led to an apparent reduction of these modifications at the HTLV-1 promoter and downstream region that correlates with a similar reduction in histone H3 and linker histone H1. Micrococcal nuclease protection analysis showed that less LTR-luciferase DNA is nucleosomal in Tax-expressing cells. Furthermore, nucleosome depletion correlated with RNA polymerase II recruitment and loss of SWI/SNF. The M47 Tax mutant, deficient in HTLV-1 transcriptional activation, was also defective for nucleosome depletion. Although this mutant formed complexes with CREB and p300 at the HTLV-1 promoter in vivo, it was unable to mediate RNA polymerase II recruitment or SWI/SNF displacement. These results support a model in which nucleosomes are depleted from the LTR and transcribed region during Tax-mediated transcriptional activation and correlate RNA polymerase II recruitment with nucleosome depletion.
Highlights
Activator of human T-cell leukemia virus type 1 (HTLV-1) transcription in part via the formation of a complex with CREB and the three CRE enhancer sequences located within the HTLV-1 promoter (6 – 8)
We and others have shown that the histone acetyltransferase activity of p300 is essential for strong HTLV-1 transcription in a chromatin context (18, 27)
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)
Summary
Activator of HTLV-1 transcription in part via the formation of a complex with CREB (or other activiting transcription factor/CREB members) and the three CRE enhancer sequences located within the HTLV-1 promoter (6 – 8). The HTLV-1 provirus is integrated into the genome of the infected host cell and assembled into nucleosomes This chromatin packaging renders promoter DNA less accessible to the binding of transcription factors and represses transcription. One mechanism for overcoming this repression is acetylation of the amino-terminal tails of the nucleosomal histones This modification is proposed to increase the accessibility of nucleosomal DNA for transcription factor binding (19 – 21). It has 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. 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). We propose that Tax, SWI/SNF, and RNAP II each plays a role in nucleosome eviction and transcriptional activation of HTLV-1 transcription
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