TALE technology holds great promise in serving as a useful tool to decipher the functionality of genetic elements and in serving as a means to selectively switch on or off genes for therapeutic purpose. In the effort to selectively switch on gene expression using TALE technology, recent studies from two independent laboratories have demonstrated that robust and synergistic gene activation can be achieved using multiple TALE activators. Here we report that this synergistic effect could be further potentiated by up to 11-fold with a novel class of TALEbased activators, TBP-TALE. We demonstrated the potentiation capability of TBP-TALEs using two classical examples of silent, cell-type restricted genes, IL-2 and GM-CSF, in diverse cell lines at both the transcriptional and translational level. These unique TBP-based activators seem to function synergistically with the conventional VP64-TALEs on both genes and on a variety of cell lines that have been tested, indicating their universal potentiation activity in a diverse intracellular environment. The demonstrated potency of TBP-TALEs in synergizing with other VP64 activators to selectively switch on the expression of immunoregulatory genes such as IL-2 and GM-CSF has direct implications for targeted cancer immunotherapy and other similar applications. Although our studies, together with two recent publications, have clearly shown that multiple VP64-TALE activators alone or in combination with TBP-TALE can act synergistically to switch on silenced genes, the detailed mechanism of such a synergistic action has not been fully elucidated. One report has suggested that TALE activators can be designed with negligible regard for chromatin structure. However, based on extensive characterization of both the IL-2 and GM-CSF promoters, it is possible that their proximal and/or core promoter regions require extensive chromatin remodeling to activate gene expression. In supporting this notion, our data indicate that the robust TALE-mediated activation on the IL-2 promoter was in part due to altered chromatin accessibility possibly attributed to the action of VP64-TALE activators in collaboration with TBP-TALE directed initiation of transcription. As transcriptional initiation begins with the recruitment of TBP, it is plausible that targeted binding of TBP-TALE to the TATA box in cytokine gene promoters can bypass this rate limiting initial step of transcription for a silenced gene and facilitate mechanisms directed by VP64-TALEs such as, displacing or repositioning the nucleosome to allow for exclusive access of TALE activators to the promoter regulatory regions. In addition, other cooperative interactions between TBP and VP64-TALEs may also contribute to their synergistic activation on the cytokine genes. Potent transcriptional activators like VP16, in which our study uses four copies of it, interact with multiple components.