Muscle-Specific Histone H3K36 Dimethyltransferase SET-18 Shortens Lifespan of Caenorhabditis elegans by Repressing daf-16a Expression

Mounting evidence shows that histone methylation, a typical epigenetic mark, is crucial for gene expression regulation during aging. Decreased trimethylation of Lys 36 on histone H3 (H3K36me3) in worms and yeast is reported to shorten lifespan. The function of H3K36me2 in aging remains unclear. In this study, we identified Caenorhabditis elegans SET-18 as a histone H3K36 dimethyltransferase. SET-18 deletion extended lifespan and increased oxidative stress resistance, dependent on daf-16 activity in the insulin/IGF pathway. In set-18 mutants, transcription of daf-16 isoform a (daf-16a) was specifically upregulated. Accordingly, a decrease in H3K36me2 on daf-16a promoter was observed. Muscle-specific expression of SET-18 increased in aged worms (day 7 and day 11), attributable to elevation of global H3K36me2 and inhibition of daf-16a expression. Consequently, longevity was shortened. These findings suggested that chromatic repression mediated by tissue-specific H3K36 dimethyltransferase might be detrimental to lifespan and may have implications in human age-related diseases. [Display omitted] •SET-domain protein SET-18 is specifically expressed in muscle and activated in old worm•SET-18 shortens lifespan through insulin/IGF pathway and daf-16 activity•SET-18 is a H3K36 dimethyltransferase and represses daf-16a by H3K36me2 modification•Activated SET-18 in old age elevates global H3K36me2 and inhibits daf-16a expression Su et al. report that a muscle-specific H3K36 dimethyltransferase SET-18 is activated in aged worm. SET-18 shortens lifespan by repressing daf-16a promoter via H3K36me2 modification. Activation of SET-18 in old age (days 7 and 11) is responsible for increased global H3K36me2 in chromatin and then represses daf-16a transcription and promotes aging of worms.