The chromatin factors SET-26 and HCF-1 oppose the histone deacetylase HDA-1 in longevity and gene regulation in C. elegans [CUT&RUN]

SET-26, HCF-1, and HDA-1 are highly conserved chromatin factors with key roles in development and aging. Here we present mechanistic insights into how these factors regulate gene expression and modulate longevity in C. elegans. We show that SET-26 and HCF-1 cooperate to regulate a common set of genes, and both antagonize the histone deacetylase HDA-1 to limit longevity. We propose a model in which SET-26 recruits HCF-1 to chromatin in somatic cells, where they stabilize each other at the promoters of a subset of genes, particularly mitochondrial function genes, and regulate their expression. HDA-1 opposes SET-26 and HCF-1 on the regulation of a subset of their common target genes and in longevity. Our findings suggest that SET-26, HCF-1, and HDA-1 comprise a mechanism to fine-tune gene expression and longevity and likely have important implications for the mechanistic understanding of how these factors function in diverse organisms, particularly in aging biology. CUT&RUN chromatin binding profiles of C. elegans proteins SET-26, HCF-1, and HDA-1 at day 1 of adulthood in somatic-only or whole worm samples, in set-26(tm2467) or hcf-1(pk924) mutant backgrounds. Profiles were obtained using CRISPR knock-in strains for each factor. Two replicates are included for each experiment, and normalization tracks (either antibody background or H3 immunoprecipitated in parallel) are included for each experiment.