Chromatin disruption and histone acetylation in regulation of the human immunodeficiency virus type 1 long terminal repeat by thyroid hormone receptor

The human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) controls the expression of HIV-1 viral genes and thus viral propagation and pathology. Numerous host factors participate in the regulation of the LTR promoter, including thyroid hormone (T(3)) receptor (TR). In vitro, TR can bind to the promoter region containing the NF-kappa B and Sp1 binding sites. Using the frog oocyte as a model system for chromatin assembly mimicking that in somatic cells, we demonstrated that TR alone and TR/RXR (9-cis retinoic acid receptor) can bind to the LTR in vivo independently of T(3). Consistent with their ability to bind the LTR, both TR and TR/RXR can regulate LTR activity in vivo. In addition, our analysis of the plasmid minichromosome shows that T(3)-bound TR disrupts the normal nucleosomal array structure. Chromatin immunoprecipitation assays with anti-acetylated-histone antibodies revealed that unliganded TR and TR/RXR reduce the local histone acetylation levels at the HIV-1 LTR while T(3) treatment reverses this reduction. We further demonstrated that unliganded TR recruits corepressors and at least one histone deacetylase. These results suggest that chromatin remodeling, including histone acetylation and chromatin disruption, is important for T(3) regulation of the HIV-1 LTR in vivo.     

HIV-1 Tat directly binds to NFkappaB enhancer sequence: role in viral and cellular gene expression

HIV-1 Tat protein reprograms cellular gene expression of infected as well as uninfected cells apart from its primary function of transactivating HIV-1 long terminal repeat (LTR) promoter by binding to a nascent RNA stem–loop structure known as the transactivator response region (TAR). Tat also induces chromatin remodeling of proviral LTR-mediated gene expression by recruiting histone acetyl transferases to the chromatin, which results in histone acetylation. Furthermore several studies have shown convincing evidence that Tat can transactivate HIV-1 gene expression in the absence of TAR, the molecular mechanism of which remains to be elucidated. Here we show a direct interaction of Tat with nuclear factor kappa B (NFκB) enhancer, a global regulatory sequence for many cellular genes both in vitro and in vivo. This interaction not only provides a novel molecular basis to explain TAR-independent transactivation in HIV-1, but also points toward the potential mechanism of Tat- mediated modulation of cellular genes.     

An array of positioned nucleosomes potentiates thyroid hormone receptor action in vivo

The assembly of the genome into chromatin imposes a poorly understood set of rules and constraints on action by regulatory factors. We investigated the role played by chromatin infrastructure in enabling an acute response of the Xenopus TRbetaA gene to thyroid hormone receptor (TR), an extensively studied member of the nuclear hormone receptor superfamily. We found that in addition to the known TR response element (TRE) in the promoter, full range regulation required an upstream enhancer that contained multiple nonconsensus TREs and augmented ligand action at high receptor levels. An array of translationally positioned nucleosomes formed over the TRbetaA locus in vivo; unliganded TR engaged this array in linker DNA between two nucleosomes and via TREs on the surface of histone octamers. Remarkably, assembly of enhancer DNA into mature chromatin potentiated binding by TR to its target response elements and enabled a greater range of regulation by TR than was observed on immature chromatin templates. Because assembly of enhancer DNA into chromatin increased TR binding to the nonconsensus TREs, we hypothesize that chromatin disruption targeted by liganded TR to the enhancer may lead to receptor release from the template and to an attenuation of response to hormone.