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

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.