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Molecular and Cellular Biology, April 2008, p. 2825-2839, Vol. 28, No. 8
0270-7306/08/$08.00+0     doi:10.1128/MCB.02076-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

DOT1L/KMT4 Recruitment and H3K79 Methylation Are Ubiquitously Coupled with Gene Transcription in Mammalian Cells{triangledown}

David J. Steger,2 Martina I. Lefterova,2 Lei Ying,1 Aaron J. Stonestrom,3 Michael Schupp,2 David Zhuo,2 Adam L. Vakoc,1 Ja-Eun Kim,4 Junjie Chen,4 Mitchell A. Lazar,2 Gerd A. Blobel,1* and Christopher R. Vakoc1*

Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104,1 Institute for Diabetes, Obesity, and Metabolism and Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,2 University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,3 Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 065204

Received 19 November 2007/ Returned for modification 18 December 2007/ Accepted 28 January 2008

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.

* Corresponding author. Mailing address for Gerd A. Blobel: Division of Hematology, Abramson Research Center 315A, The Children's Hospital of Philadelphia, 3400 Civic Center Blvd., Philadelphia, PA 19104. Phone: (215) 590-3988. Fax: (215) 590-4834. E-mail: blobel{at}email.chop.edu. Mailing address for Christopher R. Vakoc: Division of Hematology, Abramson Research Center 315A, The Children's Hospital of Philadelphia, 3400 Civic Center Blvd., Philadelphia, PA 19104. Phone: (215) 590-4461. Fax: (215) 590-4834. E-mail: vakoc{at}email.chop.edu

{triangledown} Published ahead of print on 19 February 2008.

Molecular and Cellular Biology, April 2008, p. 2825-2839, Vol. 28, No. 8
0270-7306/08/$08.00+0     doi:10.1128/MCB.02076-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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