DOT1L suppresses nuclear RNAi originating from enhancer elements in Caenorhabditis elegans

Abstract

Methylation of histone H3 on lysine 79 (H3K79) by DOT1L is associated with actively transcribed genes. Earlier, we described that 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, reduction in ZFP-1 levels has long been associated with lower efficiency of RNA interference (RNAi) triggered by exogenous double-stranded RNA (dsRNA), but the reason for this is not clear. Here, we demonstrate that DOT1L suppresses bidirectional transcription, including that producing enhancer RNAs, thereby preventing dsRNA formation and ectopic RNAi. This ectopic elevation of endogenous dsRNA may engage the Dicer complex and, therefore, limit efficiency of exogenous RNAi. Our insight provides a novel perspective on the underlying mechanisms of DOT1L function in development, neural activity, and cancer.