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Publication

Shortening the Half-Life of Cas9 Maintains Its Gene Editing Ability and Reduces Neuronal Toxicity.

Su Yang | Shihua Li | Xiao-Jiang Li

Cell reports | 2018

Virus-mediated expression of CRISPR/Cas9 is commonly used for genome editing in animal brains to model or treat neurological diseases, but the potential neurotoxicity of overexpressing bacterial Cas9 in the mammalian brain remains unknown. Through RNA sequencing (RNA-seq) analysis, we find that virus-mediated expression of Cas9 influences the expression of genes involved in neuronal functions. Reducing the half-life of Cas9 by tagging with geminin, whose expression is regulated by the cell cycle, maintains the genome editing capacity of Cas9 but significantly alleviates neurotoxicity. Thus, modification of Cas9 by shortening its half-life can help develop CRISPR/Cas9-based therapeutic approaches for treating neurological disorders.

Pubmed ID: 30517854 RIS Download

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Associated grants

Agency: NIH HHS, United States
Id: P51 OD011132
Agency: NINDS NIH HHS, United States
Id: R01 NS095181
Agency: NINDS NIH HHS, United States
Id: R01 NS095279
Agency: NINDS NIH HHS, United States
Id: R21 NS106120
Agency: NINDS NIH HHS, United States
Id: R01 NS101701
Agency: NINDS NIH HHS, United States
Id: R01 NS036232
Agency: NINDS NIH HHS, United States
Id: P30 NS055077

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This is a list of tools and resources that we have found mentioned in this publication.

Ensembl (tool)

RRID:SCR_002344

Collection of genome databases for vertebrates and other eukaryotic species with DNA and protein sequence search capabilities. Used to automatically annotate genome, integrate this annotation with other available biological data and make data publicly available via web. Ensembl tools include BLAST, BLAT, BioMart and the Variant Effect Predictor (VEP) for all supported species.

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GENEWIZ (tool)

RRID:SCR_003177

Commercial organization for research and development genomics services and technical support to researchers.

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STAR (tool)

RRID:SCR_004463

Software performing alignment of high-throughput RNA-seq data. Aligns RNA-seq reads to reference genome using uncompressed suffix arrays.

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SnpEff (tool)

RRID:SCR_005191

Genetic variant annotation and effect prediction software toolbox that annotates and predicts effects of variants on genes (such as amino acid changes). By using standards, such as VCF, SnpEff makes it easy to integrate with other programs.

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Systems Transcriptional Activity Reconstruction (tool)

RRID:SCR_005622

A next-generation web-based application that aims to provide an integrated solution for both visualization and analysis of deep-sequencing data, along with simple access to public datasets.

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QIAGEN (tool)

RRID:SCR_008539

A commercial organization which provides assay technologies to isolate DNA, RNA, and proteins from any biological sample. Assay technologies are then used to make specific target biomolecules, such as the DNA of a specific virus, visible for subsequent analysis.

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GENCODE (tool)

RRID:SCR_014966

Human and mouse genome annotation project which aims to identify all gene features in the human genome using computational analysis, manual annotation, and experimental validation.

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DESeq2 (tool)

RRID:SCR_015687

Software package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.

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