Durable and reversible epigenetic programming of human hematopoietic stem cells as a platform for modulation of platelet function.

Transient RNA-delivered DNA methylation epigenome editors induce heritable ITGB3 silencing in primary human hematopoietic stem cells, persisting through self-renewal and megakaryocytic differentiation.

• Why it matters: Programmable epigenome editing could modulate gene expression without changing DNA, but how durably it can program human HSCs and their platelet-lineage progeny was unclear.
• What they did: The authors used DNA methylation-based epigenome editors delivered transiently as RNA to target ITGB3 in primary human HSCs, then assessed persistence, platelet aggregation, and locus-specific reversibility via targeted demethylation.
• The result: ITGB3 silencing impaired aggregation of in vitro-derived platelets, was partially reversed by targeted demethylation, and remained stable 4 months after transplantation into mice, supporting durable, reversible programming and broader gene targeting.

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