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

Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10021, USA.
Cell (Impact Factor: 32.24). 07/2005; 121(6):873-85. DOI: 10.1016/j.cell.2005.04.031
Source: PubMed


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.

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Available from: C. David Allis, Mar 25, 2015
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    • "Of note, H3K14 and H4K16 are major acetylation targets for GCN5 and MOF, respectively [32] [35] [37] [55] [60]. Additionally, MOF depletion in drosophila or human cells resulted in a genome-wide loss of H4K16Ac [32] [37] [61] [62]. In our study, we did not investigate interactions of histone demethylases with St8sia4 promoter. "
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    ABSTRACT: Overfeeding causes rapid synaptic remodeling in hypothalamus feeding circuits. Polysialylation of cell surface molecules is a key step in this neuronal rewiring and allows normalization of food intake. Here we examined the role of hypothalamic polysialylation in the long-term maintenance of body weight, and deciphered the molecular sequence underlying its nutritional regulation. We found that upon high fat diet (HFD), reduced hypothalamic polysialylation exacerbated the diet-induced obese phenotype in mice. Upon HFD, the histone acetyltransferase MOF was rapidly recruited on the St8sia4 polysialyltransferase-encoding gene. Mof silencing in the mediobasal hypothalamus of adult mice prevented activation of the St8sia4 gene transcription, reduced polysialylation, altered the acute homeostatic feeding response to HFD and increased the body weight gain. These findings indicate that impaired hypothalamic polysialylation contribute to the development of obesity, and establish a role for MOF in the brain control of energy balance.
    Molecular Metabolism 09/2014; 3(6). DOI:10.1016/j.molmet.2014.05.006
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    • "This is also in accordance with a previous study showing that LAF4, like AF4 and AF5Q31, interacts with AF9/ENL protein, positive transcription elongation factor b (P-TEFb) and histone-H3 methyltransferase DOT1L [41]. In further support of Laf4 function as a transcription regulator, overexpression of Laf4 in cortical cells led to an increase in BTAF1 RNA polymerase II (Btaf1), part of the pre-initiation transcription factor II D complex [42], and Max gene associated (Mga) which binds to the transcription factor Max, a facultative component of the MLL1 complex [43]. This suggests that Laf4 likely acts in collaboration with other transcription factors or chromatin remodellers to control gene transcription. "
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    ABSTRACT: Members of the AFF (AF4/FMR2) family of putative transcription factors are involved in infant acute leukaemia and intellectual disability (ID), although very little is known about their transcriptional targets. For example, deletion of human lymphoid nuclear protein related to AF4/AFF member 3 (LAF4/AFF3) is known to cause severe neurodevelopmental defects, and silencing of the gene is also associated with ID at the folate-sensitive fragile site (FSFS) FRA2A; yet the normal function of this gene in the nervous system is unclear. The aim of this study was to further investigate the function of Laf4 in the brain by focusing on its role in the cortex. By manipulating expression levels in organotypic slices, we demonstrate here that Laf4 is required for normal cellular migration in the developing cortex and have subsequently identified Mdga2, an important structural protein in neurodevelopment, as a target of Laf4 transcriptional activity. Furthermore, we show that the migration deficit caused by loss of Laf4 can be partially rescued by Mdga2 over-expression, revealing an important functional relationship between these genes. Our study demonstrates the key transcriptional role of Laf4 during early brain development and reveals a novel function for the gene in the process of cortical cell migration relevant to the haploinsufficiency and silencing observed in human neurodevelopmental disorders.
    PLoS ONE 08/2014; 9(8):e105933. DOI:10.1371/journal.pone.0105933 · 3.23 Impact Factor
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    • "Supporting this hypothesis, MLL has been shown to directly bind to the promoter regions of a subset of Hox genes. At these promoters, MLL recruits large multiprotein complex capable of depositing methylation and acetylation marks associated with active transcription (19,20). Hox gene expression is initiated normally in Mll-knockout mice, but is not sustained past embryonic day 10.5 leading to embryonic lethality (2). "
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    ABSTRACT: MLL, the trithorax ortholog, is a well-characterized histone 3 lysine 4 methyltransferase that is crucial for proper regulation of the Hox genes during embryonic development. Chromosomal translocations, disrupting the Mll gene, lead to aggressive leukemia with poor prognosis. However, the functions of MLL in cellular processes like cell-cycle regulation are not well studied. Here we show that the MLL has a regulatory role during multiple phases of the cell cycle. RNAi-mediated knockdown reveals that MLL regulates S-phase progression and, proper segregation and cytokinesis during M phase. Using deletions and mutations, we narrow the cell-cycle regulatory role to the C subunit of MLL. Our analysis reveals that the transactivation domain and not the SET domain is important for the S-phase function of MLL. Surprisingly, disruption of MLL–WRAD interaction is sufficient to disrupt proper mitotic progression. These mitotic functions of WRAD are independent of SET domain of MLL and, therefore, define a new role of WRAD in subset of MLL functions. Finally, we address the overlapping and unique roles of the different SET family members in the cell cycle.
    Nucleic Acids Research 05/2014; 42(12). DOI:10.1093/nar/gku458 · 9.11 Impact Factor
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