Moderate and in some instances, completely failed to activate gene expression. Further analysis found that the activation of an epigenetically silenced gene required a combination of epigenetic modifiers acting together with a TALE activator, while a single TALE was unable to stimulate such a combinatorial effect and was thus inefficient in activating the silenced Oct4 promoter. Recently, two studies have demonstrated that this limitation can be overcome by targeting multiple TALE activators to a gene promoter for synergistic gene activation. Furthermore, these studies reveal that targeting of TALE activators to open chromatin regions within gene promoters are not a requirement for successful gene activation, suggesting that TALEs can override repressive chromatin structures through cooperative binding to a gene promoter. However, some key elements in the promoter regions, such as the TATA-box and transcription initiation site, have not been fully evaluated in the context of TALE technology for gene activation purposes. In eukaryotic cells, initiation of transcription begins with the recognition and binding of promoter-specific transcriptional activators to their cognate DNA response elements within a gene promoter. An activator functions as a platform to recruit and assemble chromatin remodelers and components of the basal transcriptional machinery. More specifically, activators recruit the TATA-box binding protein to gene promoters, resulting in the formation of the preinitiation complex comprised of TBP-associated factors, transcription factor II proteins, and RNA Pol II to stimulate mRNA transcription. Consequently, TBP binding to the TATA box is the rate limiting step in transcriptional initiation. Hence, we rationed that targeted recruitment of TBP using a linked TALE DNA-binding domain to a particular TATA box could lead to transcriptional initiation of the selected gene by bypassing this crucial rate-limiting step. Several studies have shown that artificial recruitment of non-classical activators coupled with classical activators can synergize gene expression. To date, no study has examined the utility of such a strategy using TALE activators for targeted activation of silent gene expression. Therefore, we aimed to interrogate TALE activation potential utilizing the combined action of chimeric TBP and VP64-TALE activators applied to a classical example of gene silencing observed within T-cell biology illustrated by IL-2 and GM-CSF genes. Our data shows that TALE fused to TBP acts synergistically with other VP64-TALE activators and this combination is significantly more efficacious than multiple TALE activators alone in activating expression of IL-2 and GM-CSF in diverse non-immune cells in which both genes are otherwise completely silenced. Chromatin analysis revealed that the gene activation was due in part to displacement of a distinctly positioned nucleosome.