DOT1L suppresses nuclear RNAi originating from enhancer elements in Caenorhabditis elegans

Abstract

Summary 7Methylation of histone H3 lysine 79 (H3K79) by DOT1L is associated with actively 8 transcribed genes. We have previously demonstrated that DOT-1.1, the Caenorhabditis 9 elegans DOT1L homologue, cooperates with the chromatin-binding protein ZFP-1 10 (homologue of the mammalian AF10) to negatively modulate transcription of highly and 11 widely expressed target genes. Also, zfp-1 deficiency has been associated with reduced 12 RNA interference (RNAi) response. In addition, in MLL-rearranged leukemia, H3K79 13 methylation at homeobox genes was shown to antagonize repressive chromatin marks. 14 Here, we connect these various manifestations of DOT1L function. We demonstrate that 15 DOT1L suppresses transcription at enhancers, thereby preventing double-stranded 16 RNA (dsRNA) formation and ectopic histone H3 lysine 9 (H3K9) methylation. Moreover, 17we show that lethality of dot-1.1 mutant worms is suppressed by mutations in the RNAi 18 pathway, suggesting ectopic activation of endogenous RNAi in the absence of DOT1L.