Abstract
Methylation of histone H3 lysine 79 by DOT1L is associated with actively transcribed genes. DOT-1.1, the Caenorhabditis elegans DOT1L homologue, cooperates with the chromatin-binding protein ZFP-1 (AF10 homologue) to negatively modulate transcription of highly and widely expressed target genes. Also, zfp-1 deficiency is linked to reduced RNA interference response. In addition, in MLL-rearranged leukemia, H3K79 methylation at homeobox genes antagonizes repressive chromatin marks. Here, we connect these various manifestations of DOT1L function. We demonstrate that DOT1L suppresses transcription at enhancers, thereby preventing double-stranded RNA formation and ectopic histone H3 lysine 9 methylation. Moreover, we show that lethality of dot-1.1 mutant worms is suppressed by mutations in the RNAi pathway, suggesting ectopic activation of endogenous RNAi in the absence of DOT1L. Since DOT1L is conserved and similarly prevents H3K9 methylation in C. elegans and mammals, our observations point to a possible link between nuclear RNAi and H3K9 methylation in higher organisms.