biostudies-literatureLev IEuropean Research CouncilAdelis FoundationIsrael Science FoundationPaul G. Allen Family FoundationNIH HHSe40448https://www.ebi.ac.uk/biostudies/studies/S-EPMC6417860biostudies-literatureUnknown8In <i>Caenorhabditis elegans</i>, RNA interference (RNAi) responses can transmit across generations via small RNAs. RNAi inheritance is associated with Histone-3-Lysine-9 tri-methylation (H3K9me3) of the targeted genes. In other organisms, maintenance of silencing requires a feed-forward loop between H3K9me3 and small RNAs. Here, we show that in <i>C. elegans</i> not only is H3K9me3 unnecessary for inheritance, the modification's function depends on the identity of the RNAi-targeted gene. We found an asymmetry in the requirement for H3K9me3 and the main worm H3K9me3 methyltransferases, SET-25 and SET-32. Both methyltransferases promote heritable silencing of the foreign gene <i>gfp</i>, but are dispensable for silencing of the endogenous gene <i>oma-1</i>. Genome-wide examination of heritaeLifeH3K9me3 is required for inheritance of small RNAs that target a unique subset of newly evolved genes.PMC6417860P40 OD0104401339/1733562401430001000Gingold HLev IRechavi OfalseH3K9me3 is required for inheritance of small RNAs that target a unique subset of newly evolved genes.In <i>Caenorhabditis elegans</i>, RNA interference (RNAi) responses can transmit across generations via small RNAs. RNAi inheritance is associated with Histone-3-Lysine-9 tri-methylation (H3K9me3) of the targeted genes. In other organisms, maintenance of silencing requires a feed-forward loop between H3K9me3 and small RNAs. Here, we show that in <i>C. elegans</i> not only is H3K9me3 unnecessary for inheritance, the modification's function depends on the identity of the RNAi-targeted gene. We found an asymmetry in the requirement for H3K9me3 and the main worm H3K9me3 methyltransferases, SET-25 and SET-32. Both methyltransferases promote heritable silencing of the foreign gene <i>gfp</i>, but are dispensable for silencing of the endogenous gene <i>oma-1</i>. Genome-wide examination of herita2019-01-01T00:00:00Z2019 Mar2026-04-30T02:45:34.201Z2026-04-07T15:43:21.574ZS-EPMC64178603086907510.7554/eLife.40448