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Mol. Cell. Biol. doi:10.1128/MCB.02076-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells

Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104; Institute for Diabetes, Obesity, and Metabolism, and Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Department of Oncology, Yale University School of Medicine, New Haven, CT 06520

^* To whom correspondence should be addressed. Email: vakoc{at}email.chop.edu.

	Abstract

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 well with enrichment of H3K79 di-/tri-methylation. Furthermore, Dot1l-mutant fibroblasts lacked H3K79 di-/tri-methylation at all sites examined, indicating that DOT1L is the sole enzyme responsible for these marks. Importantly, we identified 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 mono-methylation into di-/tri-methylation correlated with the transition from low- to high-level gene transcription. We also observed enrichment of H3K79 mono-methylation at intergenic regions occupied by DNA-binding transcriptional activators. Our findings highlight several similarities between the patterning of H3K4 and 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.