Confirming the Pro-longevity Effects of H3K4me3-deficient set-2 Mutants in Extending Lifespan in C. elegans

Abstract

The COMPASS chromatin complex, which trimethylates lysine 4 on histone H3 (H3K4me3), regulates lifespan in Caenorhabditis elegans. Knockdown or partial loss-of-function of SET-2, a member of the COMPASS complex, extends the lifespan of worms. However, recent observations suggested that full loss of SET-2 methyltransferase activity via deletion of its active site reduces lifespan, indicating the degree of COMPASS inhibition may be critical to its effects on aging. To further explore these inconsistencies, we examined set-2 longevity across a range of interventions from weak to full inhibition. Via CRISPR/Cas9 genome-editing, we made two new set-2 mutants, a new genocopy of the most commonly used set-2(ok952) allele for mild set-2 inhibition, and a full set-2 genomic deletion. We found that both new strains (partial and null) and RNAi show a lifespan extension in C. elegans fed HT115 E. coli. However, neither mutant was long-lived in C. elegans fed OP50-1 E. coli. These data confirm that the previous lifespan extension observed in set-2(ok952) mutants was indeed the result of set-2 inhibition (and not a secondary linked mutation generated in the original strain). These data also indicate that a diet-dependent mechanism might contribute to the regulation of lifespan under H3K4me3 deficiency and highlight how COMPASS-mediated longevity involves a complex interaction between chromatin state and environment.