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Although multiple strategies have been developed to increase knock\u2010in 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\u2010in 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\u2010homologous 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\u2010fidelity gene knock\u2010in, offering valuable mechanistic clues and actionable epigenetic targets to gene editing for basic research and therapeutic translation.<\/jats:p>","DOI":"10.1111\/cpr.70285","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T08:57:16Z","timestamp":1791536236000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chromatin Modifications Orchestrate\n                    <scp>DNA<\/scp>\n                    Repair Pathway Choice: Epigenetics Strategies for Enhancing\n                    <scp>CRISPR<\/scp>\n                    \u2013Cas9\u2010Mediated Knock\u2010In Efficiency"],"prefix":"10.1111","volume":"59","author":[{"given":"Xin","family":"Chen","sequence":"first","affiliation":[{"name":"School of Disaster and Emergency Medicine, Faculty of Medicine Tianjin 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