The histone H3 lysine 79 methyltransferase DOT1L/KMT4 can promote an oncogenic 
pattern of gene expression through binding with several MLL fusion partners 
found in acute leukemia. However, the normal function of DOT1L in mammalian gene 
regulation is poorly understood. Here we report that DOT1L recruitment is 
ubiquitously coupled with active transcription in diverse mammalian cell types. 
DOT1L preferentially occupies the proximal transcribed region of active genes, 
correlating with enrichment of H3K79 di- and trimethylation. Furthermore, Dot1l 
mutant fibroblasts lacked H3K79 di- and trimethylation at all sites examined, 
indicating that DOT1L is the sole enzyme responsible for these marks. 
Importantly, we identified chromatin immunoprecipitation (ChIP) assay conditions 
necessary for reliable H3K79 methylation detection. ChIP-chip tiling arrays 
revealed that levels of all degrees of genic H3K79 methylation correlate with 
mRNA abundance and dynamically respond to changes in gene activity. Conversion 
of H3K79 monomethylation into di- and trimethylation correlated with the 
transition from low- to high-level gene transcription. We also observed 
enrichment of H3K79 monomethylation at intergenic regions occupied by 
DNA-binding transcriptional activators. Our findings highlight several 
similarities between the patterning of H3K4 methylation and that of H3K79 
methylation in mammalian chromatin, suggesting a widespread mechanism for 
parallel or sequential recruitment of DOT1L and MLL to genes in their normal 
"on" state.