DOT1L/KMT4 Recruitment and H3K79 Methylation Are Ubiquitously Coupled with Gene Transcription in Mammalian Cells
- 1 April 2008
- journal article
- research article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 28 (8), 2825-2839
- https://doi.org/10.1128/mcb.02076-07
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 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.This publication has 59 references indexed in Scilit:
- Interplay of Chromatin Modifiers on a Short Basic Patch of Histone H4 Tail Defines the Boundary of Telomeric HeterochromatinMolecular Cell, 2007
- Recognition of Trimethylated Histone H3 Lysine 4 Facilitates the Recruitment of Transcription Postinitiation Factors and Pre-mRNA SplicingMolecular Cell, 2007
- Selective Anchoring of TFIID to Nucleosomes by Trimethylation of Histone H3 Lysine 4Cell, 2007
- Active and Repressive Chromatin Are Interspersed without Spreading in an Imprinted Gene Cluster in the Mammalian GenomeMolecular Cell, 2007
- A Chromatin Landmark and Transcription Initiation at Most Promoters in Human CellsCell, 2007
- High-Resolution Profiling of Histone Methylations in the Human GenomeCell, 2007
- Methylation of Lysine 4 on Histone H3: Intricacy of Writing and Reading a Single Epigenetic MarkMolecular Cell, 2007
- Structural Basis for the Methylation State-Specific Recognition of Histone H4-K20 by 53BP1 and Crb2 in DNA RepairCell, 2006
- A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem CellsCell, 2006
- Systematic variation in gene expression patterns in human cancer cell linesNature Genetics, 2000