DNA origami: a tool to evaluate and harness transcription factors.

Abstract

Alongside other players, such as CpG methylation and the "histone code," transcription factors (TFs) represent a key feature of gene regulation. TFs are implicated in critical cellular processes, ranging from cell death, growth, and differentiation, up to intranuclear signaling of steroid and other hormones, physical entities, and hypoxia regulation. Notwithstanding an extensive body of research in this field, several questions and therapeutic options remain unanswered and unexplored, respectively. Of note, many of these TFs represent therapeutic targets, which are either difficult to be pharmacologically tackled or are still not drugged via traditional approaches, such as small-molecule inhibition. Upon providing a brief overview of TFs, we focus herein on how synthetic biology/medicine could assist in their study as well as their therapeutic targeting. Specifically, we contend that DNA origami, i.e., a novel synthetic DNA nanotechnological approach, represents an excellent synthetic biology/medicine tool to accomplish the above goals, since it can harness several vital characteristics of DNA: DNA polymerization, DNA complementarity, DNA "programmability," and DNA "editability." In doing so, DNA origami can be applied to study TF dynamics during DNA transcription, to elucidate xeno-nucleic acids with distinct scaffolds and unconventional base pairs, and to use TFs as competitors of oncogene-engaged promoters. Overall, because of their potential for high-throughput design and their favorable pharmacodynamic and pharmacokinetic properties, DNA origami can be a novel armory for TF-related drug design. Last, we discuss future trends in the field, such as RNA origami and innovative DNA origami-based therapeutic delivery approaches.