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

Steger, D. J., Lefterova, M. I., Ying, L., Stonestrom, A. J., Schupp, M., Zhuo, D., Vakoc, A. L., Kim, J. E., Chen, J., Lazar, M. A., Blobel, G. A., Vakoc, C. R. (2008) DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells. Molecular and Cellular Biology, 28 (8). pp. 2825-2839. ISSN 02707306 (ISSN)

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. Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Item Type:	Paper
Uncontrolled Keywords:	histone H3 histone methyltransferase lysine messenger RNA mixed lineage leukemia protein protein DOT1L protein KMT4 transcription factor unclassified drug acute leukemia animal cell article carcinogenesis cell differentiation chromatin chromatin immunoprecipitation controlled study fibroblast gene control gene expression gene function genetic transcription mammal cell mouse nonhuman priority journal protein function protein methylation Adipocytes Animals Antigens CD36 Cells Cultured GATA1 Transcription Factor Globins Histones Methylation Methyltransferases Mice Mice Inbred C57BL PPAR gamma Sodium Dodecyl Sulfate Transcription Genetic Mammalia
Subjects:	diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > histone diseases & disorders > cancer > cancer types > leukemia bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor diseases & disorders > cancer > cancer types
CSHL Authors:	Vakoc, Christopher R.
Communities:	CSHL labs > Vakoc lab
Depositing User:	CSHL Librarian
Date:	2008
Date Deposited:	19 Mar 2012 19:28
Last Modified:	13 Mar 2013 20:21
PMCID:	PMC2293113
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/25393

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