Physical Association and Coordinate Function of the H3 K4 Methyltransferase MLL1 and the H4 K16 Acetyltransferase MOF

Abstract

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.

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

“…During the formation of this complex, MLL is cut by taspase into an N-terminal (MLL N ) and a C-terminal (MLL C ) fragment. 25 MLL C then associates with at least four proteins, that is, the histone acetyltransferase MYST1(MOF), 26 and WDR5, RBBP5 and ASH2L, to ensure histone modification and methyltransferase activity. 27 The MLL N fragment has a binding site for MEN1 at the N-terminal end and both recruit PSIP1(LEDGF).…”

“…MLL N also contains a CxxC domain, which specifically binds to unmethylated DNA. 29 Transcription factors such as p53 and CTNNB1(b-catenin) are most likely to recruit the MLL complex to initiate RNA synthesis, 26,30 and specific genes, such as the HOX genes, seem to be more dependent on the MLL complex for chromatin modification during transcription than others. 31,32 In MLL rearrangements the breakpoint in MLL is highly conserved and all fusion partners are fused in frame, leading to a gain of function of the MLL complex.…”

MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells

“…It is now known that MYST proteins have important roles in various biological processes (Ceol and Horvitz, 2004;Kusch et al, 2004;Dou et al, 2005;Smith et al, 2005;Mendjan et al, 2006;Sykes et al, 2006;Tang et al, 2006). These enzymes have been the subjects of several excellent reviews Squatrito et al, 2006;Avvakumov and Coˆte´, 2007;Lafon et al, 2007;Rea et al, 2007;Thomas and Voss, 2007).…”

Males absent on the first (MOF): from flies to humans

“…This complex localizes to hundreds of sites along the male Xchromosome and is required to equalize X-linked gene expression between male flies, with one X-chromosome and female flies with two. Recent biochemical purifications revealed that both the Drosophila and mammalian MOF proteins reside in multi-protein complexes and that most of these interacting proteins are conserved between Drosophila and mammals (Table 2; Dou et al, 2005;Smith et al, 2005;Mendjan et al, 2006). Co-purification of four human MSL proteins (hMSL1, hMSL2, hMSL3 and hMOF) showed that the MSL (Borrow et al, 1996;Carapeti et al, 1998;Champagne et al, 1999Champagne et al, , 2001Chaffanet et al, 2000;Kitabayashi et al, 2001;Pelletier et al, 2002;Bristow and Shore, 2003;Deguchi et al, 2003;Kindle et al, 2005;Katsumoto et al, 2006;Thomas et al, 2006;Ohta et al, 2007 Abbreviation: HAT, histone acetyltransferases.…”