Cell proliferationOct 9, 2026

How DNA Packaging Changes Guide Repair Choices and Improve CRISPR Gene Insertion

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 10, 2026

Abstract

Histone modifications such as H3K36me3 and H3K9me3 are involved in DNA damage signaling and the recruitment of repair factors.

CRISPR-Cas9-mediated gene knock-in occurs at low frequencies due to reliance on homology-directed repair.
Conventional methods to improve knock-in efficiency often face technical complexity or safety concerns.
Epigenetic methods may offer a new approach to enhance knock-in efficiency by modulating chromatin states.
Histone modifications play a crucial role in influencing DNA repair pathways, including both HDR and non-homologous end joining.
Transient modulation of chromatin could shift the preference for repair pathway choice, although it presents technical challenges.

Simplified

CRISPR-Cas9-mediated precise gene knock-in relies on homology-directed repair (HDR) at low frequencies in most mammalian cells, limiting precise gene editing in both research and therapeutic applications. Although multiple strategies have been developed to increase knock-in efficiency, their application can be restricted by technical complexity, limited applicability, or potential safety concerns. In this review, we propose a shift in focus from conventional strategies toward epigenetic methods to increase knock-in efficiency. It has been proved that histone modifications such as H3K36me3, H3K9me3, H4K20me2, and H2AK15ub are involved in DNA damage signallings and the recruitment of key HDR and non-homologous end joining (NHEJ) factors. We further discuss conceptual strategies for transient chromatin modulation to bias repair pathway choice and highlight associated technical challenges and safety considerations. Together, these findings and insights highlight the essential role of histone modification in shaping chromatin states and orchestrating DNA repair dynamics. Accordingly, epigenetic regulation emerges as a compelling strategy to facilitate high-fidelity gene knock-in, offering valuable mechanistic clues and actionable epigenetic targets to gene editing for basic research and therapeutic translation.

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How DNA Packaging Changes Guide Repair Choices and Improve CRISPR Gene Insertion

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