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<p>Transgenerational epigenetic inheritance (TEI) allows epigenetic information to pass across generations through mechanisms such as small RNAs and histone modifications. Histone methylation is often deposited by SET domain-containing methyltransferases. Some SET proteins lack catalytic activity but still regulate chromatin and gene expression. Here, we characterize SET-24, a catalytically inactive SET domain protein that localizes to germline nuclei and is essential for germline immortality in <i>Caenorhabditis elegans</i>. In <i>set-24</i> mutants, small RNA-mediated epigenetic silencing is impaired. Proteomic, yeast two-hybrid, and pull-down assays show that SET-24 interacts with HCF-1, a chromatin factor linked to complexes like COMPASS, which deposits H3K4me3. Loss of SET-24 leads to increased H3K4me3 at transcription start sites of hundreds of genes. Although transcription remains largely unchanged, small RNA production is disrupted for about 30% of these genes. We propose that SET-24 preserves germline epigenetic memory by sustaining a chromatin environment that supports small RNA biogenesis across generations.</p>

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A SET domain-containing protein and HCF-1 maintain transgenerational epigenetic memory

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月9日

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  • Chenming Zeng,
  • Giulia Furlan,
  • Miguel Vasconcelos Almeida,
  • Juan C. Rueda-Silva,
  • Jonathan Price,
  • Helena Santos-Rosa,
  • Jingxiu Xu,
  • Yan Kuang,
  • Enric Cata Socias,
  • Jonas Mars,
  • Pedro Rebelo-Guiomar,
  • Meng Huang,
  • Shouhong Guang,
  • Falk Butter,
  • Eric A. Miska

摘要

Transgenerational epigenetic inheritance (TEI) allows epigenetic information to pass across generations through mechanisms such as small RNAs and histone modifications. Histone methylation is often deposited by SET domain-containing methyltransferases. Some SET proteins lack catalytic activity but still regulate chromatin and gene expression. Here, we characterize SET-24, a catalytically inactive SET domain protein that localizes to germline nuclei and is essential for germline immortality in Caenorhabditis elegans. In set-24 mutants, small RNA-mediated epigenetic silencing is impaired. Proteomic, yeast two-hybrid, and pull-down assays show that SET-24 interacts with HCF-1, a chromatin factor linked to complexes like COMPASS, which deposits H3K4me3. Loss of SET-24 leads to increased H3K4me3 at transcription start sites of hundreds of genes. Although transcription remains largely unchanged, small RNA production is disrupted for about 30% of these genes. We propose that SET-24 preserves germline epigenetic memory by sustaining a chromatin environment that supports small RNA biogenesis across generations.