Chromatin context-dependent regulation and epigenetic manipulation of prime editing Prime editing is a precise genome engineering technique that is highly influenced by the chromatin environment. This study shows that the efficiency of prime editing is strongly affected by the chromatin context, with factors such as chromatin marks (e.g., H3K79me2 and H3K9me3) playing a significant role. The researchers developed a method to map the genomic locations of integrated reporters and found that prime editing efficiency varies widely depending on the chromatin environment. They also identified HLTF as a context-dependent suppressor of prime editing. Additionally, they found that active transcriptional elongation enhances prime editing efficiency. The study also shows that epigenetic conditioning of a locus can modulate prime editing efficiency. The results suggest that chromatin context plays a crucial role in determining the success of prime editing, and that epigenetic manipulation can be used to enhance its efficiency. The study highlights the importance of understanding the chromatin environment in order to optimize the use of prime editing for genome engineering applications.Chromatin context-dependent regulation and epigenetic manipulation of prime editing Prime editing is a precise genome engineering technique that is highly influenced by the chromatin environment. This study shows that the efficiency of prime editing is strongly affected by the chromatin context, with factors such as chromatin marks (e.g., H3K79me2 and H3K9me3) playing a significant role. The researchers developed a method to map the genomic locations of integrated reporters and found that prime editing efficiency varies widely depending on the chromatin environment. They also identified HLTF as a context-dependent suppressor of prime editing. Additionally, they found that active transcriptional elongation enhances prime editing efficiency. The study also shows that epigenetic conditioning of a locus can modulate prime editing efficiency. The results suggest that chromatin context plays a crucial role in determining the success of prime editing, and that epigenetic manipulation can be used to enhance its efficiency. The study highlights the importance of understanding the chromatin environment in order to optimize the use of prime editing for genome engineering applications.