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Specific multivalent molecules boost CRISPR-mediated transcriptional activation via optimal cis-trans interaction and functional chromatin looping.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE249351 | GEO | 2024/06/01

REPOSITORIES: GEO

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Specific multivalent molecules boost CRISPR-mediated transcriptional activation via optimal cis-trans interaction and functional chromatin looping [RNA-seq]

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Specific multivalent molecules boost CRISPR-mediated transcriptional activation via optimal cis-trans interaction and functional chromatin looping [ChIA-PET]

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Specific multivalent molecules boost CRISPR-mediated transcriptional activation via optimal cis-trans interaction and functional chromatin looping.

Project description:Specific multivalent molecules boost CRISPR-mediated transcriptional activation via optimal cis-trans interaction and functional chromatin looping.

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Specific multivalent molecules boost CRISPR-mediated transcriptional activation via optimal cis-trans interaction and functional chromatin looping [RNA-seq]

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Specific multivalent molecules boost CRISPR-mediated transcriptional activation via optimal cis-trans interaction and functional chromatin looping [ChIA-PET]

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Specific multivalent molecules boost CRISPR-mediated transcriptional activation.

Project description: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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Project description:Interactions between glycans and proteins have tremendous impact in biomolecular interactions. They are important for cell-cell interactions, proliferation and much more. Here, we emphasize the glycan-mediated interactions between pathogens and host cells. Pseudomonas aeruginosa, responsible for a huge number of nosocomial infections, is especially the focus when it comes to glycan-derivatives as pathoblockers. We present a microwave assisted protecting group free synthesis of glycomonomers based on lactose, melibiose and fucose. The monomers were polymerized in a precipitation polymerization in the presence of NiPAm to form crosslinked glyco-nanogels. The influence of reaction parameters like crosslinker type or stabilizer amount was investigated. The gels were characterized in lectin binding studies using model lectins and showed size and composition-dependent inhibition of lectin binding. Due to multivalent presentation of glycans in the gel, the inhibition was clearly stronger than with unmodified saccharides, which was compared after determination of the glycan loading. First studies with Pseudomonas aeruginosa revealed a surprising influence on the secretion of virulence factors. Functional glycogels may be in the future potent alternatives or adjuvants for antibiotic treatment of infections based on glycan interactions between host and pathogen.

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