Dissecting polycomb complexes for enhanced fetal hemoglobin production.

Selective disruption of EZH2 exon 14 in PRC2 reactivates fetal hemoglobin in adult erythroid cells while preserving cell fitness.

• Why it matters: Reversing the fetal-to-adult hemoglobin switch offers a promising treatment for sickle cell disease and β-thalassemia, but broad PRC inhibition causes undesirable effects, necessitating more targeted approaches.
• What they did: Using high-density CRISPR-Cas9 mutagenesis, the study identified EZH2 exon 14 skipping (EZH2Δ14) that relieves hemoglobin repression without compromising overall cell health, and confirmed this pathway in a mouse model.
• The result: Targeting nonenzymatic domains within PRC2, such as EZH2Δ14, enables selective fetal hemoglobin induction, opening avenues for therapies that minimize side effects of broad chromatin-modifying complex inhibition.