2. Academic Validation
  3. Specific multivalent molecules boost CRISPR-mediated transcriptional activation

Specific multivalent molecules boost CRISPR-mediated transcriptional activation

  • Nat Commun. 2024 Aug 22;15(1):7222. doi: 10.1038/s41467-024-51694-y.
Rui Chen 1 2 3 4,  Xinyao Shi 1 3,  Xiangrui Yao 1 3,  Tong Gao 1 3,  Guangyu Huang 1 3,  Duo Ning 1 3,  Zemin Cao 1 3,  Youxin Xu 1 3,  Weizheng Liang 1 3 5,  Simon Zhongyuan Tian 1 2 3,  Qionghua Zhu 1 2 3 4,  Liang Fang 1 2 3 4,  Meizhen Zheng 1 2 3,  Yuhui Hu 6 7,  Huanhuan Cui 8 9 10 11,  Wei Chen 12 13 14 15
Affiliations

Affiliations

  • 1 Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
  • 2 Innovative Center for RNA Therapeutics (ICRT), School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
  • 3 Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
  • 4 Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen, China.
  • 5 Central Laboratory, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China.
  • 6 Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
  • 7 Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
  • 8 Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. cuihh@sustech.edu.cn.
  • 9 Innovative Center for RNA Therapeutics (ICRT), School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. cuihh@sustech.edu.cn.
  • 10 Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. cuihh@sustech.edu.cn.
  • 11 Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen, China. cuihh@sustech.edu.cn.
  • 12 Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. chenw@sustech.edu.cn.
  • 13 Innovative Center for RNA Therapeutics (ICRT), School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. chenw@sustech.edu.cn.
  • 14 Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. chenw@sustech.edu.cn.
  • 15 Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen, China. chenw@sustech.edu.cn.
PMID: 39174527 DOI: 10.1038/s41467-024-51694-y
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.

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