Epigenetic programming by H3K23ac defines lineage fate of Meg3+ haematopoietic stem cells and drives immune ageing

Haematopoietic stem cells (HSCs) produce all blood and immune cells throughout life, but ageing progressively impairs their function, generating excessive myeloid and megakaryocyte cells at the expense of lymphocytes. This lineage imbalance contributes to immune decline, chronic inflammation and increased disease susceptibility in the elderly, yet the underlying mechanisms remain poorly understood. Here we show that a specific Meg3+ HSC subset (CD150hiSca1hiCD24hiCD201+CD9+CD63+ long-term HSCs) expands dramatically during ageing and drives this lineage skewing. Using multi-omics profiling, we found that inflammatory signals increase H3K23ac levels in aged Meg3+ HSCs, enhancing PU.1 activity through recruitment of the reader protein TRIM24. This epigenetic mechanism promotes excessive megakaryocyte and myeloid production. Of note, disrupting H3K23ac–TRIM24 interaction in aged HSCs restored balanced lineage output and reduced inflammatory signals. Our findings reveal a key mechanism linking inflammation to HSC ageing and identify potential therapeutic targets for reversing ageing-related immune decline. Wei et al. show that Meg3+ haematopoietic stem cells (HSCs) expand upon ageing and present with an increase in H3K23ac levels observed already at middle age. Inhibiting H3K23ac ameliorates megakaryocyte/platelet and myeloid skewing in aged HSCs.