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Small-molecule Activators Specific to Adenine Base Editors through Blocking Canonical TGF-beta Pathway

ABSTRACT: Small-molecule Activators Specific to Adenine Base Editors through Blocking Canonical TGF-beta Pathway

PROVIDER: PRJNA858681 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20203763_1.fastq.gz	Fastqsanger.gz
	SRR20203763_2.fastq.gz	Fastqsanger.gz
	SRR20203764_1.fastq.gz	Fastqsanger.gz
	SRR20203764_2.fastq.gz	Fastqsanger.gz
	SRR20203765_1.fastq.gz	Fastqsanger.gz

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Small-molecule Activators Specific to Adenine Base Editors through Blocking Canonical TGF-beta Pathway

Project description:ABEs were developed to catalyze an A-to-G conversion, thus holding therapeutic potentials for treating the major class of human pathogenic SNPs. However, robust and precise editing at diverse genome loci in a controllable manner remains challenging. Here, through a high-throughput chemical screen of ~ 8,000 small molecules, we identified and validated a spectrum of small molecules that target the canonical TGF-beta pathway as ABE activators. Among those, SB505124, a selective ALK5 inhibitor, promotes ABE editing most. Treating cells with SB505124 dramatically enhanced on-target editing at multiple genome loci, including the refractory regions, while exhibiting little effect on off-target conversion on the genome, eliminating the major concern for clinical applications. Furthermore, SB505124 facilitates the editing of disease-associated genes in vitro and in vivo. Intriguingly, SB505124 serves as a specific activator by selectively promoting the activity of ABEs, rather than CBEs or Cas9. Our finding equips the ABE with precise chemical control, and more importantly, reveals a so-far-unreported role of the canonical TGF-beta pathway on gene editing.

2022-09-20 | GSE208182 | GEO

Small-molecule activators specific to adenine base editors through blocking the canonical TGF-β pathway.

Project description:Adenine base editors (ABEs) catalyze A-to-G conversions, offering therapeutic options to treat the major class of human pathogenic single nucleotide polymorphisms (SNPs). However, robust and precise editing at diverse genome loci remains challenging. Here, using high-throughput chemical screening, we identified and validated SB505124, a selective ALK5 inhibitor, as an ABE activator. Treating cells with SB505124 enhanced on-target editing at multiple genome loci, including epigenetically refractory regions, and showed little effect on off-target conversion on the genome. Furthermore, SB505124 facilitated the editing of disease-associated genes in vitro and in vivo. Intriguingly, SB505124 served as a specific activator by selectively promoting ABE activity. Mechanistically, SB505124 promotes ABE editing, at least in part, by enhancing ABE expression and modulating DNA repair-associated genes. Our findings reveal the role of the canonical transforming growth factor-β pathway in gene editing and equip ABEs with precise chemical control.

| S-EPMC9508813 | biostudies-literature

Transcriptome-wide effects of cytosine and adenine deaminases on gene expression induced by base editors

Project description:We used RNA-sequencing data to explore the transcriptome-wide effects of cytosine and adenine deaminases on gene expression induced by base editors.

2021-06-01 | GSE158693 | GEO

Targeted exon skipping with AAV-mediated split adenine base editors.

Project description:Techniques for exclusion of exons from mature transcripts have been applied as gene therapies for treating many different diseases. Since exon skipping has been traditionally accomplished using technologies that have a transient effect, it is particularly important to develop new techniques that enable permanent exon skipping. We have recently demonstrated that this can be accomplished using cytidine base editors for permanently disabling the splice acceptor of target exons. We now demonstrate the application of adenine-deaminase base editors to disrupt the conserved adenosine within splice acceptor sites for programmable exon skipping. We also demonstrate that by altering the amino acid sequence of the linker between the adenosine deaminase domain and the Cas9 nickase or by coupling the adenine base editor with a uracil glycosylase inhibitor, the DNA editing efficiency and exon skipping rates improve significantly. Finally, we developed a split base editor architecture compatible with adeno-associated viral packaging. Collectively, these results represent significant progress towards permanent in vivo exon skipping through base editing and, ultimately, a new modality of gene therapy for the treatment of genetic diseases.

2019-09-12 | GSE120125 | GEO

Precise adenine base editors that exhibit minimized cytosine catalysis

Project description:Precise adenine base editors that exhibit minimized cytosine catalysis

| PRJNA693459 | ENA

CRISPR adenine and cytosine base editors with reduced RNA off-target activities [CBE]

Project description:CRISPR-guided DNA base editors enable the efficient installation of targeted single-nucleotide changes. Cytosine or adenine base editors (CBEs or ABEs), which are fusions of cytidine or adenosine deaminases to CRISPR-Cas nickases, can efficiently induce DNA C-to-T or A-to-G alterations in DNA, respectively. We recently demonstrated that both the widely used CBE BE3 (harboring a rat APOBEC1 cytidine deaminase) and the optimized ABEmax editor can induce tens of thousands of guide RNA-independent, transcriptome-wide RNA base edits in human cells with high efficiencies. In addition, we showed the feasibility of creating SElective Curbing of Unwanted RNA Editing (SECURE)-BE3 variants that exhibit substantially reduced unwanted RNA editing activities while retaining robust and more precise on-target DNA editing. Here we describe structure-guided engineering of SECURE-ABE variants that not only possess reduced off-target RNA editing with comparable on-target DNA activities but are also the smallest Streptococcus pyogenes Cas9 (SpCas9) base editors described to date. In addition, we tested CBEs composed of cytidine deaminases other than APOBEC1 and found that human APOBEC3A (hA3A) cytidine deaminase CBE induces substantial transcriptome-wide RNA base edits with high efficiencies. By contrast, a previously described “enhanced” A3A (eA3A) cytidine deaminase CBE or a human activation-induced cytidine deaminase (hAID) CBE induce substantially reduced or near background levels of RNA edits. In sum, our work describes broadly useful SECURE-ABE and -CBE base editors and reinforces the importance of minimizing RNA editing activities of DNA base editors for research and therapeutic applications.

2019-07-11 | GSE129893 | GEO

CRISPR adenine and cytosine base editors with reduced RNA off-target activities [ABE]

2019-07-11 | GSE129889 | GEO

Targeted exon skipping with AAV-mediated split adenine base editors.

Project description:Targeted exon skipping with AAV-mediated split adenine base editors.

| PRJNA491711 | ENA

Bimodal Adenine and Cytosine CRISPR Base Editing on DNA

Project description:Adenine and cytosine base editors (ABEs and CBEs) represent a new genome editing technology that allows the programmable installation of A-to-G or C-to-T alterations on DNA. We engineered Streptococcus pyogenes Cas9-based adenine and cytosine base editor (SpACE) that enables efficient simultaneous introduction of A-to-G and C-to-T substitutions in the same base editing window on DNA.

2020-07-02 | GSE137411 | GEO

CRISPR adenine and cytosine base editors with reduced RNA off-target activities

Project description:CRISPR adenine and cytosine base editors with reduced RNA off-target activities

| PRJNA533102 | ENA