Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto, 606-8502, Japan.
Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Yoshida-Ushinomaecho, Sakyo-ku, Kyoto, 606-8501, Japan.
Chem Rec. 2021 Jun;21(6):1374-1384. doi: 10.1002/tcr.202000158. Epub 2020 Dec 17.
To maintain the functions of living organisms, cells have developed complex gene regulatory networks. Transcription factors have a central role in spatiotemporal control of gene expression and this has motivated us to develop artificial transcription factors that mimic their function. We found that three functions could be mimicked by applying our chemical approaches: i) efficient delivery into organelles that contain target DNA, ii) specific DNA binding to the target genomic region, and iii) regulation of gene expression by interaction with other transcription coregulators. We chose pyrrole-imidazole polyamides (PIPs), sequence-selective DNA binding molecules, as DNA binding domains, and have achieved each of the required functions by introducing other functional moieties. The developed artificial transcription factors have potential as chemical tools that can be used to artificially modulate gene expression to enable cell fate control and to correct abnormal gene regulation for therapeutic purposes.
为了维持生物体的功能，细胞已经发展出复杂的基因调控网络。转录因子在基因表达的时空控制中起着核心作用，这促使我们开发出模拟其功能的人工转录因子。我们发现，通过应用我们的化学方法可以模拟三种功能：i）有效地递送到含有靶 DNA 的细胞器中，ii）特异性地与靶基因组区域结合，以及 iii）通过与其他转录共激活因子相互作用来调节基因表达。我们选择吡咯-咪唑聚酰胺（PIPs）作为 DNA 结合结构域，这是一种序列特异性的 DNA 结合分子，并通过引入其他功能基团来实现每种必需的功能。开发的人工转录因子具有作为化学工具的潜力，可用于人工调节基因表达，以实现细胞命运控制，并纠正异常基因调节以达到治疗目的。
