A SET domain-containing protein and HCF-1 maintain transgenerational epigenetic memory
- 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
2026-01-09
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.