DOT-1.1 (DOT1L) deficiency in leads to small RNA-dependent gene activation.

Methylation of histone H3 at lysine 79 (H3K79) is conserved from yeast to humans and is accomplished by Dot1 (disruptor of telomeric silencing-1) methyltransferases. The enzyme DOT-1.1 and its interacting partners are similar to the mammalian DOT1L (Dot1-like) complex. The DOT-1.1 complex has been functionally connected to RNA interference. Specifically, we have previously shown that embryonic and larval lethality of mutant worms deficient in H3K79 methylation was suppressed by mutations in the RNAi pathway genes responsible for generation () and function () of primary small interfering RNAs (siRNAs). This suggests that mutant lethality is dependent on the enhanced production of some siRNAs. We have also found that this lethality is suppressed by a loss-of-function of CED-3, a conserved apoptotic protease. Here, we describe a comparison of gene expression and primary siRNA production changes between control and deletion mutant embryos. We found that elevated antisense siRNA production occurred more often at upregulated than downregulated genes. Importantly, gene expression changes were dependent on RDE-4 in both instances. Moreover, the upregulated group, which is potentially activated by ectopic siRNAs, was enriched in protease-coding genes. Our findings are consistent with a model where in the absence of H3K79 methylation there is a small RNA-dependent activation of protease genes, which leads to embryonic and larval lethality. DOT1 enzymes' conservation suggests that the interplay between H3K79 methylation and small RNA pathways may exist in higher organisms.