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<p>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 <i>Meg3</i><sup>+</sup> HSC subset (CD150<sup>hi</sup>Sca1<sup>hi</sup>CD24<sup>hi</sup>CD201<sup>+</sup>CD9<sup>+</sup>CD63<sup>+</sup> 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 <i>Meg3</i><sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • Ni Wei,
  • Huiwen Zhan,
  • Yujun Deng,
  • Min Liu,
  • Yao Xiao,
  • Yanqiu Gong,
  • Xiaodong Wang,
  • Pengbo Guan,
  • Xiaoxian Lou,
  • Yusi Xie,
  • Yuemeng Wang,
  • Zhonghan Li,
  • Lunzhi Dai,
  • Hongbo Hu,
  • Huiyuan Zhang

摘要

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.