The chromatin context differently impacts prime editors and base editors and controls the fidelity and purity of base editing.

In human cellular systems, heterochromatin shaped by the KRAB/KAP-1/HP-1 axis mostly hinders prime editors more than base editors, with prime-editing guide RNA extensions driving the effect.

• Why it matters: Chromatin state can alter editing performance, but how it differentially affects prime versus base editing efficiency, fidelity, and byproduct purity at matched genomic targets was unclear.
• What they did: The study used isogenic human target sites with controlled epigenetic remodeling factors, comparing prime editors and base editors while varying non-heritable KRAB/KAP-1/HP-1 heterochromatin versus heritable DNMT3A/DNMT3L-linked states.
• The result: Base editors were frequently unhindered or more active in heterochromatin than euchromatin, whereas prime editors were not; base-editing byproducts also varied with epigenetic context, informing fidelity and purity expectations.

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