Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF.
A stable complex containing MLL1 and MOF has been immunoaffinity purified from a human cell line that stably expresses an epitope-tagged WDR5 subunit. Stable interactions between MLL1 and MOF were confirmed by reciprocal immunoprecipitation, cosedimentation, and cotransfection analyses, and interaction sites were mapped to MLL1 C-terminal and MOF zinc finger domains. The purified complex has a robust MLL1-mediated histone methyltransferase activity that can effect mono-, di-, and trimethylation of H3 K4 and a MOF-mediated histone acetyltransferase activity that is specific for H4 K16. Importantly, both activities are required for optimal transcription activation on a chromatin template in vitro and on an endogenous MLL1 target gene, Hox a9, in vivo. These results indicate an activator-based mechanism for joint MLL1 and MOF recruitment and targeted methylation and acetylation and provide a molecular explanation for the closely correlated distribution of H3 K4 methylation and H4 K16 acetylation on active genes.
Dou
Yali
Y
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10021, USA.
Milne
Thomas A
TA
Tackett
Alan J
AJ
Smith
Edwin R
ER
Fukuda
Aya
A
Wysocka
Joanna
J
Allis
C David
CD
Chait
Brian T
BT
Hess
Jay L
JL
Roeder
Robert G
RG
D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000502:physiology*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008840:Microfilament Proteins / Q000302:isolation & purification / Q000502:physiology; D009097:Multienzyme Complexes / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein; D011519:Proto-Oncogenes / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D016335:Zinc Fingers / Q000235:genetics / Q000502:physiology
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C497422:KMT2A protein, human; D008840:Microfilament Proteins; D009097:Multienzyme Complexes; D014157:Transcription Factors; C097899:homeobox protein HOXA9; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C496552:KAT8 protein, human