Degree of Recruitment of DOT1L to MLL-AF9 Defines Level of H3K79 Di- and Tri-methylation on Target Genes and Transformation Potential Journal Article


Authors: Kuntimaddi, A; Achille, N. J.; Thorpe, J.; Lokken, A. A.; Singh, R.; Hemenway, C. S.; Adli, M.; Zeleznik-Le, N. J.; Bushweller, J. H.
Article Title: Degree of Recruitment of DOT1L to MLL-AF9 Defines Level of H3K79 Di- and Tri-methylation on Target Genes and Transformation Potential
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.
Journal Title: Cell reports
Volume: 11
Issue: 5
ISSN: 2211-1247
Publisher: Unknown  
Journal Place: United States
Date Published: 2015
Start Page: 808
End Page: 820
Language: eng
DOI/URL:
Notes: LR: 20150509; CI: Copyright (c) 2015; GR: R01 CA155328/CA/NCI NIH HHS/United States; JID: 101573691; NIHMS678448; PMCR: 2016/05/05 00:00; 2014/12/19 [received]; 2015/02/18 [revised]; 2015/03/30 [accepted]; 2015/04/23 [aheadofprint]; ppublish