The role of DOT1L methyltransferase in controlling the noncoding transcriptome

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The broad goal of our research is to understand how gene expression is regulated during animal development. Our specific interest is in finding natural regulators of endogenous double-stranded RNA production and nuclear RNA interference. In this regard, we are focusing on the relationship between RNA interference and the histone H3 lysine 79 DOT1L methyltransferase complex. A connection between the DOT1L interacting partner ZFP-1 (AF10 in mammals) and RNAi in C. elegans was suggested by genetic experiments 13-15 years ago. To understand this connection, my laboratory undertook molecular and genomic studies of ZFP-1 and DOT1L. These studies not only confirmed the connection to RNAi, but also provided novel insights about the conserved role of DOT1L in transcription regulation. The DOT1L enzyme is essential for mammalian development and has been implicated in the pathogenesis of leukemia and breast cancer. However, the exact role of DOT1L in gene regulation is not clear. Preliminary work from our lab has begun to reveal this role; we have discovered that DOT1L and H3K79 methylation globally suppress non-coding RNA transcription in C. elegans, including that of antisense and enhancer RNAs. Our preliminary data strongly suggest ectopic dsRNA formation and small RNA production upon DOT1L loss-of-function. Our main goals are: 1) to detect and characterize these dsRNA and small RNA molecules in C. elegans; 2) to explore the possibility that the dsRNA suppressing function of DOT1L is conserved in mammals, and 3) to investigate the mechanism of transcription regulation by DOT1L in development using the C. elegans and zebrafish systems.