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Cell Rep. 2015 May 5;11(5):808-20. doi: 10.1016/j.celrep.2015.04.004. Epub 2015 Apr 23.

Degree of recruitment of DOT1L to MLL-AF9 defines level of H3K79 Di- and tri-methylation on target genes and transformation potential.

Author information

1
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
2
Oncology Institute, Department of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
3
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
4
Oncology Institute, Department of Pediatrics, Loyola University Chicago, Maywood, IL 60153, USA.
5
Oncology Institute, Department of Medicine, Loyola University Chicago, Maywood, IL 60153, USA. Electronic address: nzelezn@luc.edu.
6
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA. Electronic address: jhb4v@virginia.edu.

Abstract

The MLL gene is a common target of chromosomal translocations found in human leukemia. MLL-fusion leukemia has a consistently poor outcome. One of the most common translocation partners is AF9 (MLLT3). MLL-AF9 recruits DOT1L, a histone 3 lysine 79 methyltransferase (H3K79me1/me2/me3), leading to aberrant gene transcription. We show that DOT1L has three AF9 binding sites and present the nuclear magnetic resonance (NMR) solution structure of a DOT1L-AF9 complex. We generate structure-guided point mutations and find that they have graded effects on recruitment of DOT1L to MLL-AF9. Chromatin immunoprecipitation sequencing (ChIP-seq) analyses of H3K79me2 and H3K79me3 show that graded reduction of the DOT1L interaction with MLL-AF9 results in differential loss of H3K79me2 and me3 at MLL-AF9 target genes. Furthermore, the degree of DOT1L recruitment is linked to the level of MLL-AF9 hematopoietic transformation.

PMID:
25921540
PMCID:
PMC4426023
DOI:
10.1016/j.celrep.2015.04.004
[Indexed for MEDLINE]
Free PMC Article

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