Moz and Retinoic Acid Coordinately Regulate H3K9 Acetylation, Hox Gene Expression, and Segment Identity

Voss, Anne K.; Collin, Caitlin; Dixon, Mathew P.; Thomas, Tim

doi:10.1016/j.devcel.2009.10.006

Cited by 148 publications

(187 citation statements)

References 69 publications

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“…In line with recent data indicating that MYST3 primarily acetylates histone 3, at least at Hox loci (22), we observed significantly reduced H3 acetylation but unchanged H4 acetylation in these cells lacking MYST4 ( Figure 2C). …”

Section: Figuresupporting

confidence: 79%

Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome–like phenotype and hyperactivated MAPK signaling in humans and mice

Kraft¹,

Cirstea²,

Voss³

et al. 2011

J. Clin. Invest.

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112

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Epigenetic regulation of gene expression, through covalent modification of histones, is a key process controlling growth and development. Accordingly, the transcription factors regulating these processes are important targets of genetic diseases. However, surprisingly little is known about the relationship between aberrant epigenetic states, the cellular process affected, and their phenotypic consequences. By chromosomal breakpoint mapping in a patient with a Noonan syndrome-like phenotype that encompassed short stature, blepharoptosis, and attention deficit hyperactivity disorder, we identified haploinsufficiency of the histone acetyltransferase gene MYST histone acetyltransferase (monocytic leukemia) 4 (MYST4), as the underlying cause of the phenotype. Using acetylation, whole genome expression, and ChIP studies in cells from the patient, cell lines in which MYST4 expression was knocked down using siRNA, and the Myst4 querkopf mouse, we found that H3 acetylation is important for neural, craniofacial, and skeletal morphogenesis, mainly through its ability to specifically regulating the MAPK signaling pathway. This finding further elucidates the complex role of histone modifications in mammalian development and adds what we believe to be a new mechanism to the pathogenic phenotypes resulting from misregulation of the RAS signaling pathway.

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Section: Figuresupporting

confidence: 79%

Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome–like phenotype and hyperactivated MAPK signaling in humans and mice

Kraft¹,

Cirstea²,

Voss³

et al. 2011

J. Clin. Invest.

Self Cite

112

View full text Add to dashboard Cite

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“…Semiquantitative PCR also suggested that MLL was less recruited onto the HOX regions when CD34 þ cells were co-transfected with MOZ siRNA (Supplementary Figure 4a). In addition, it has been recently reported that the absence of Moz in mice results in reduced association of Mll1 with Hox gene loci and reduced Hox gene expression, suggesting that Moz may recruit Mll1 to Hox gene loci (Voss et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

“…Knockdown of MLL or MOZ inhibits MOZ recruitment and the epigenetic marks from HOX promoters due to the enzymatic activities of MOZ or MLL. Furthermore, it was recently shown a possible functional link between Moz and Mll1 in mouse embryos (Voss et al, 2009). In mice, Moz seems to be required for normal Hox gene expression and body segment identity specification, like TrxG proteins, but Moz is also required for the association of Mll1 with Hox gene loci in vivo.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

et al. 2010

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MOZ and MLL, encoding a histone acetyltransferase (HAT) and a histone methyltransferase, respectively, are targets for recurrent chromosomal translocations found in acute myeloblastic or lymphoblastic leukemia. In MOZ (MOnocytic leukemia Zinc-finger protein)/CBP-or mixed lineage leukemia (MLL)-rearranged leukemias, abnormal levels of HOX transcription factors have been found to be critical for leukemogenesis. We show that MOZ and MLL cooperate to regulate these key genes in human cord blood CD34 þ cells. These chromatinmodifying enzymes interact, colocalize and functionally cooperate, and both are recruited to multiple HOX promoters. We also found that WDR5, an adaptor protein essential for lysine 4 trimethylation of histone H3 (H3K4me3) by MLL, colocalizes and interacts with MOZ. We detected the binding of the HAT MOZ to H3K4me3, thus linking histone methylation to acetylation. In CD34 þ cells, depletion of MLL causes release of MOZ from HOX promoters, which is correlated to defective histone activation marks, leading to repression of HOX gene expression and alteration of commitment of CD34 þ cells into myeloid progenitors. Thus, our results unveil the role of the interaction between MOZ and MLL in CD34 þ cells in which both proteins have a critical role in hematopoietic cell-fate decision, suggesting a new molecular mechanism by which MOZ or MLL deregulation leads to leukemogenesis.

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“…Interestingly, in vitro, recombinant Enok did not acetylate H3K9 or H3K14 (Supplemental Fig. S1C), which are the targets of its mammalian and yeast homologs (Howe et al 2001;Ullah et al 2008;Voss et al 2009), suggesting that Enok uniquely prefers H3K23 as the substrate among these three residues. Nevertheless, we cannot exclude the possibility that Enok may have additional targets or that other factors may interact with Enok to expand its substrate specificity in vivo.…”

Section: Enok Acetylates H3k23 In Vitro and In Vivomentioning

confidence: 99%

Histone acetyltransferase Enok regulates oocyte polarization by promoting expression of the actin nucleation factor spire

et al. 2014

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KAT6 histone acetyltransferases (HATs) are highly conserved in eukaryotes and have been shown to play important roles in transcriptional regulation. Here, we demonstrate that the Drosophila KAT6 Enok acetylates histone H3 Lys 23 (H3K23) in vitro and in vivo. Mutants lacking functional Enok exhibited defects in the localization of Oskar (Osk) to the posterior end of the oocyte, resulting in loss of germline formation and abdominal segments in the embryo. RNA sequencing (RNA-seq) analysis revealed that spire (spir) and maelstrom (mael), both required for the posterior localization of Osk in the oocyte, were down-regulated in enok mutants. Chromatin immunoprecipitation showed that Enok is localized to and acetylates H3K23 at the spir and mael genes. Furthermore, Gal4-driven expression of spir in the germline can largely rescue the defective Osk localization in enok mutant ovaries. Our results suggest that the Enok-mediated H3K23 acetylation (H3K23Ac) promotes the expression of spir, providing a specific mechanism linking oocyte polarization to histone modification.

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Moz and Retinoic Acid Coordinately Regulate H3K9 Acetylation, Hox Gene Expression, and Segment Identity

Cited by 148 publications

References 69 publications

Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome–like phenotype and hyperactivated MAPK signaling in humans and mice

Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome–like phenotype and hyperactivated MAPK signaling in humans and mice

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

Histone acetyltransferase Enok regulates oocyte polarization by promoting expression of the actin nucleation factor spire

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