ArticleMolecular therapy. Nucleic acids2019
The Chromatin Structure of CRISPR-Cas9 Target DNA Controls the Balance between Mutagenic and Homology-Directed Gene-Editing Events.
Article in Molecular therapy. Nucleic acids, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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36 citing papers in PubMed, 54 citations in OpenAlex.
- CRISPR/Cas9-based repair of a heterozygous HNF1A mutation in patient-derived hiPSCs.Human genetics · 2026Article
- Efficient Endogenous Tagging in the Sea Urchin,bioRxiv : the preprint server for biology · 2026Article
- Cyanine-modified ssODNs enhance CRISPR-Cas9 HDR in stem cell embryo models via chromatin and chemical modulation.Nature communications · 2026Article
- Advances and challenges of precision epigenetic therapy in treating genomic imprinting diseases.Translational pediatrics · 2026Review
- Engineering precision zebrafish alleles of human disease.bioRxiv : the preprint server for biology · 2025Article
- Comparative Analysis of Methods for Assessing On-Target Gene Editing Efficiencies.Methods and protocols · 2025Article
- Beyond a few bases: methods for large DNA insertion and gene targeting in plants.The Plant journal : for cell and molecular biology · 2025Review
- Precision genome editing using combinatorial viral vector delivery of CRISPR-Cas9 nucleases and donor DNA constructs.Nucleic acids research · 2025Article
- Small Molecule MIF Modulation Enhances Ferroptosis by Impairing DNA Repair Mechanisms.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Article
- Trichostatin A for Efficient CRISPR-Cas9 Gene Editing of Human Pluripotent Stem Cells.The CRISPR journal · 2023Article
- Genome Editing in Ferret Airway Epithelia Mediated by CRISPR/Nucleases Delivered with Amphiphilic Shuttle Peptides.Human gene therapy · 2023Article
- Precise homology-directed installation of large genomic edits in human cells with cleaving and nicking high-specificity Cas9 variants.Nucleic acids research · 2023Article
- Implementation of ubiquitous chromatin opening elements as artificial integration sites for CRISPR/Cas9-mediated knock-in in mammalian cells.Engineering in life sciences · 2023Article
- New advances in CRISPR/Cas-mediated precise gene-editing techniques.Disease models & mechanisms · 2023Review
- A culture platform to study quiescent hematopoietic stem cells following genome editing.Cell reports methods · 2022Article
- Decorating chromatin for enhanced genome editing using CRISPR-Cas9.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Double-strand break toxicity is chromatin context independent.Nucleic acids research · 2022Article
- Improving Homology-Directed Repair in Genome Editing Experiments by Influencing the Cell Cycle.International journal of molecular sciences · 2022Review
- Beta HPV Deregulates Double-Strand Break Repair.Viruses · 2022Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Gene editing based on homology-directed repair (HDR) depends on donor DNA templates and programmable nucleases, e.g., RNA-guided CRISPR-Cas9 nucleases. However, next to inducing HDR involving the mending of chromosomal double-stranded breaks (DSBs) with donor DNA substrates, programmable nucleases also yield gene disruptions, triggered by competing non-homologous end joining (NHEJ) pathways. It is, therefore, imperative to identify parameters underlying the relationship between these two outcomes in the context of HDR-based gene editing. Here we implemented quantitative cellular systems, based on epigenetically regulated isogenic target sequences and donor DNA of viral, non-viral, and synthetic origins, to investigate gene-editing outcomes resulting from the interaction between different chromatin conformations and donor DNA structures. We report that, despite a significantly higher prevalence of NHEJ-derived events at euchromatin over Krüppel-associated box (KRAB)-impinged heterochromatin, HDR frequencies are instead generally less impacted by these alternative chromatin conformations. Hence, HDR increases in relation to NHEJ when open euchromatic target sequences acquire a closed heterochromatic state, with donor DNA structures determining, to some extent, the degree of this relative increase in HDR events at heterochromatin. Finally, restricting nuclease activity to HDR-permissive G2 and S phases of the cell cycle through a Cas9-Geminin construct yields lower, hence more favorable, NHEJ to HDR ratios, independently of the chromatin structure.
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