Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
Molecules. 2020 Apr 20;25(8):1902. doi: 10.3390/molecules25081902.
The recent developments in the delivery and design of transcription factors put their therapeutic applications within reach, exemplified by cell replacement, cancer differentiation and T-cell based cancer therapies. The success of such applications depends on the efficacy and precision in the action of transcription factors. The biophysical and genetic characterization of the paradigmatic prokaryotic repressors, LacI and TetR and the designer transcription factors, transcription activator-like effector (TALE) and CRISPR-dCas9 revealed common principles behind their efficacy, which can aid the optimization of transcriptional activators and repressors. Further studies will be required to analyze the linkage between dissociation constants and enzymatic activity, the role of phase separation and squelching in activation and repression and the long-range interaction of transcription factors with epigenetic regulators in the context of the chromosomes. Understanding these mechanisms will help to tailor natural and synthetic transcription factors to the needs of specific applications.
近年来转录因子的传递和设计方面的进展使它们的治疗应用成为可能，其例子包括细胞替代、癌症分化和基于 T 细胞的癌症治疗。此类应用的成功取决于转录因子作用的功效和精度。典范原核阻遏物 LacI 和 TetR 以及设计转录因子转录激活因子样效应物 (TALE) 和 CRISPR-dCas9 的生物物理和遗传特性揭示了它们功效背后的共同原则，这有助于优化转录激活剂和阻遏物。需要进一步研究来分析离解常数和酶活性之间的联系、相分离和抑制在激活和抑制中的作用以及转录因子与染色质中表观遗传调节剂的长程相互作用。理解这些机制将有助于根据特定应用的需求来定制天然和合成转录因子。
