What does this research mean for the field?

CRISPR-Cas9 off-target mutations and translocations are highly heterogeneous between individual cells and exhibit distinct, context-dependent profiles across different organs, which are modulated by epigenetic features and often missed by bulk analyses. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

To establish workflows for mapping CRISPR-Cas9 off-target cleavage and structural variations at single-cell resolution and characterize tissue-specific editing outcomes in vivo.

August 29, 2026Nature CommunicationsOpen Access

Single-cell and in vivo profiling reveal heterogeneous and organ-specific CRISPR-Cas9 off-target and translocation outcomes

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Authors

AMAlexandra Madsen NSNiklas Selfjord MMMarta Martínez-Lage

Discussion

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Overview

Preclinical study reveals heterogeneous, organ-specific CRISPR-Cas9 off-target cuts and translocations in mouse models, highlighting the need for localized safety assessments.

Key Points

To establish workflows for mapping CRISPR-Cas9 off-target cleavage and structural variations at single-cell resolution and characterize tissue-specific editing outcomes in vivo.
Electroporated mouse embryos and embryonic stem cells to clonally analyze single-cell off-target mutations and chromosomal translocations.
Integrated single-cell editing data with chromatin accessibility, gene transcription, and DNA methylation measurements.
Profiled off-target spectra, DNA repair pathway utilization, indel patterns, and translocation frequencies across multiple tissues in Cas9-inducible mouse models.
Individual cells exhibited unique off-target mutations and translocation profiles that were undetected in standard bulk sequencing analyses.
Sequence-independent epigenetic features significantly influenced cleavage, with Cas9 showing preferential editing in regions marked by open chromatin and lower DNA methylation.
Cas9-inducible mice displayed distinct, organ-specific off-target profiles, DNA repair pathway choices, indel distributions, and markedly divergent translocation propensities.

Cite This Study

Madsen et al. (2026) studied this question.

synapsesocial.com/papers/6a9299088e5d7d1fc0c10c1e https://doi.org/10.1038/s41467-026-77144-5

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August 29, 2026Nature CommunicationsOpen Access

Single-cell and in vivo profiling reveal heterogeneous and organ-specific CRISPR-Cas9 off-target and translocation outcomes

View Full Paper

Ask AI

Bookmark

Authors

AMAlexandra Madsen NSNiklas Selfjord MMMarta Martínez-Lage

Discussion

Member takes

Overview

Preclinical study reveals heterogeneous, organ-specific CRISPR-Cas9 off-target cuts and translocations in mouse models, highlighting the need for localized safety assessments.

Key Points

To establish workflows for mapping CRISPR-Cas9 off-target cleavage and structural variations at single-cell resolution and characterize tissue-specific editing outcomes in vivo.
Electroporated mouse embryos and embryonic stem cells to clonally analyze single-cell off-target mutations and chromosomal translocations.
Integrated single-cell editing data with chromatin accessibility, gene transcription, and DNA methylation measurements.
Profiled off-target spectra, DNA repair pathway utilization, indel patterns, and translocation frequencies across multiple tissues in Cas9-inducible mouse models.
Individual cells exhibited unique off-target mutations and translocation profiles that were undetected in standard bulk sequencing analyses.
Sequence-independent epigenetic features significantly influenced cleavage, with Cas9 showing preferential editing in regions marked by open chromatin and lower DNA methylation.
Cas9-inducible mice displayed distinct, organ-specific off-target profiles, DNA repair pathway choices, indel distributions, and markedly divergent translocation propensities.

Cite This Study

Madsen et al. (2026) studied this question.

synapsesocial.com/papers/6a9299088e5d7d1fc0c10c1e https://doi.org/10.1038/s41467-026-77144-5

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