Specific multivalent molecules boost CRISPR-mediated transcriptional activation

Rui Chen, Xinyao Shi, Xiangrui Yao, Tong Gao, Guangyu Huang, Duo Ning, Zemin Cao, Youxin Xu, Weizheng Liang, Simon Zhongyuan Tian, Qionghua Zhu, Liang Fang, Meizhen Zheng, Yuhui Hu, Huanhuan Cui () and Wei Chen ()
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Rui Chen: Southern University of Science and Technology
Xinyao Shi: Southern University of Science and Technology
Xiangrui Yao: Southern University of Science and Technology
Tong Gao: Southern University of Science and Technology
Guangyu Huang: Southern University of Science and Technology
Duo Ning: Southern University of Science and Technology
Zemin Cao: Southern University of Science and Technology
Youxin Xu: Southern University of Science and Technology
Weizheng Liang: Southern University of Science and Technology
Simon Zhongyuan Tian: Southern University of Science and Technology
Qionghua Zhu: Southern University of Science and Technology
Liang Fang: Southern University of Science and Technology
Meizhen Zheng: Southern University of Science and Technology
Yuhui Hu: Southern University of Science and Technology
Huanhuan Cui: Southern University of Science and Technology
Wei Chen: Southern University of Science and Technology

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract CRISPR/Cas-based transcriptional activators can be enhanced by intrinsically disordered regions (IDRs). However, the underlying mechanisms are still debatable. Here, we examine 12 well-known IDRs by fusing them to the dCas9-VP64 activator, of which only seven can augment activation, albeit independently of their phase separation capabilities. Moreover, modular domains (MDs), another class of multivalent molecules, though ineffective in enhancing dCas9-VP64 activity on their own, show substantial enhancement in transcriptional activation when combined with dCas9-VP64-IDR. By varying the number of gRNA binding sites and fusing dCas9-VP64 with different IDRs/MDs, we uncover that optimal, rather than maximal, cis-trans cooperativity enables the most robust activation. Finally, targeting promoter-enhancer pairs yields synergistic effects, which can be further amplified via enhancing chromatin interactions. Overall, our study develops a versatile platform for efficient gene activation and sheds important insights into CRIPSR-based transcriptional activators enhanced with multivalent molecules.

Date: 2024
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DOI: 10.1038/s41467-024-51694-y

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