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<p>Histone modifiers are crucial for instructing multiple-stage cellular differentiation, yet the mechanisms underlying their temporal precision remain enigmatic. Here, we demonstrate that the H3K27 demethylase Kdm6b acts as an epigenetic regulator, coordinating stepwise motor neuron (MN) differentiation through sequential partnerships with stage-specific transcription factors (TFs). Genome-wide profiling reveals a progressive gain in Kdm6b occupancy, especially at distal regulatory elements, as differentiation proceeds. Kdm6b dynamically remodels chromatin landscapes by coordinating H3K27me3 removal with H3K27ac and H3K4me1 acquisition, thereby enabling timed gene activation from MN specification to maturation. Stage-specific inhibition of Kdm6b compromises the ordered expression of developmental genes. Mechanistically, Kdm6b interacts with temporal TFs over time to ensure precise transcriptional control and MN differentiation. Our work elucidates how a single epigenetic regulator achieves temporal fidelity of stepwise MN development, providing insight into epigenetic regulation of developmental timing.</p>

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Kdm6b-mediated epigenetic coordination of temporal precision during motor neuron differentiation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月26日

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  • Haihan Ren,
  • Qicheng Liu,
  • Bingqian Li,
  • Xuetong Yu,
  • Dan Liang,
  • Shuangling Li,
  • Bing Pan,
  • Qian Gao,
  • Wenhong Deng,
  • Jun-Ma Yu,
  • Wenxian Wang

摘要

Histone modifiers are crucial for instructing multiple-stage cellular differentiation, yet the mechanisms underlying their temporal precision remain enigmatic. Here, we demonstrate that the H3K27 demethylase Kdm6b acts as an epigenetic regulator, coordinating stepwise motor neuron (MN) differentiation through sequential partnerships with stage-specific transcription factors (TFs). Genome-wide profiling reveals a progressive gain in Kdm6b occupancy, especially at distal regulatory elements, as differentiation proceeds. Kdm6b dynamically remodels chromatin landscapes by coordinating H3K27me3 removal with H3K27ac and H3K4me1 acquisition, thereby enabling timed gene activation from MN specification to maturation. Stage-specific inhibition of Kdm6b compromises the ordered expression of developmental genes. Mechanistically, Kdm6b interacts with temporal TFs over time to ensure precise transcriptional control and MN differentiation. Our work elucidates how a single epigenetic regulator achieves temporal fidelity of stepwise MN development, providing insight into epigenetic regulation of developmental timing.