Specific multivalent molecules boost CRISPR-mediated transcriptional activation.

CRISPR-Cas Systems Transcriptional Activation Humans Promoter Regions, Genetic RNA, Guide, CRISPR-Cas Systems / genetics HEK293 Cells Binding Sites Chromatin / metabolism Clustered Regularly Interspaced Short Palindromic Repeats Enhancer Elements, Genetic

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
22 Aug 2024
Historique:
received: 14 01 2024
accepted: 15 08 2024
medline: 23 8 2024
pubmed: 23 8 2024
entrez: 22 8 2024
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-51694-y PMID: 39174527
pubmed: 39174527
doi: 10.1038/s41467-024-51694-y
pii: 10.1038/s41467-024-51694-y
doi:

Substances chimiques

RNA, Guide, CRISPR-Cas Systems 0
Chromatin 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

7222

Informations de copyright

© 2024. The Author(s).

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Auteurs

Rui Chen (R)

Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Innovative Center for RNA Therapeutics (ICRT), School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen, China.
ORCID: 0000-0003-3821-0436

Xinyao Shi (X)

Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.

Xiangrui Yao (X)

Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.

Tong Gao (T)

Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.

Guangyu Huang (G)

Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.

Duo Ning (D)

Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.

Zemin Cao (Z)

Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.

Youxin Xu (Y)

Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.

Weizheng Liang (W)

Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Central Laboratory, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China.

Simon Zhongyuan Tian (SZ)

Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Innovative Center for RNA Therapeutics (ICRT), School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
ORCID: 0000-0003-2934-4088

Qionghua Zhu (Q)

Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Innovative Center for RNA Therapeutics (ICRT), School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen, China.
ORCID: 0000-0002-8057-202X

Liang Fang (L)

Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Innovative Center for RNA Therapeutics (ICRT), School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen, China.
ORCID: 0000-0003-4502-1756

Meizhen Zheng (M)

Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Innovative Center for RNA Therapeutics (ICRT), School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
ORCID: 0000-0001-5569-1812

Yuhui Hu (Y)

Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
ORCID: 0000-0002-5210-5301

Huanhuan Cui (H)

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.
Innovative Center for RNA Therapeutics (ICRT), School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. cuihh@sustech.edu.cn.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. cuihh@sustech.edu.cn.
Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen, China. cuihh@sustech.edu.cn.
ORCID: 0000-0002-6190-6135

Wei Chen (W)

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.
Innovative Center for RNA Therapeutics (ICRT), School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. chenw@sustech.edu.cn.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. chenw@sustech.edu.cn.
Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen, China. chenw@sustech.edu.cn.
ORCID: 0000-0003-3263-1627

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Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Extinction de l'expression des gènes › Systèmes CRISPR-Cas › Specific multivalent molecules boost...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Activation de la transcription › Specific multivalent molecules boost...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Specific multivalent molecules boost...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Éléments de régulation transcriptionnelle › Régions promotrices (génétique) › Specific multivalent molecules boost...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN non traduit › Petit ARN non traduit › Systèmes CRISPR-Cas, ARN, guide › Specific multivalent molecules boost...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › Specific multivalent molecules boost...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Sites de fixation › Specific multivalent molecules boost...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Structures de chromosome › Chromatine › Specific multivalent molecules boost...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Séquences répétées en tandem › Clustered regularly interspaced short palindromic repeats › Specific multivalent molecules boost...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Éléments de régulation transcriptionnelle › Éléments activateurs (génétique) › Specific multivalent molecules boost...