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The histone methyltransferase activity of MLL1 is dispensable for hematopoiesis and leukemogenesis

ABSTRACT: Despite correlations between histone methyltransferase (HMT) activity and gene regulation, direct evidence that HMT activity is responsible for gene activation is sparse. We address the role of the HMT activity for MLL1, a histone H3 lysine 4 (H3K4) methyltransferase critical for maintaining hematopoietic stem cells (HSCs). Here we show that the SET domain and thus HMT activity of MLL1 is dispensable for maintaining HSCs and for supporting leukemogenesis driven by the MLL-AF9 fusion oncoprotein. Upon Mll1 deletion, histone H4 lysine 16 (H4K16) acetylation was selectively depleted at MLL1 target genes in conjunction with reduced transcription. Surprisingly, inhibition of SIRT1 was sufficient to prevent the loss of H4K16 acetylation and the reduction in MLL1 target gene expression. Thus, recruited MOF activity, and not the intrinsic HMT activity of MLL1, is central for the maintenance of HSC target genes. In addition, this work reveals a role for SIRT1 in opposing MLL1 function.

ORGANISM(S): Mus musculus

PROVIDER: GSE56456 | GEO | 2014/04/03

SECONDARY ACCESSION(S): PRJNA243374

REPOSITORIES: GEO

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The histone methyltransferase activity of MLL1 is dispensable for hematopoiesis and leukemogenesis

Project description:Despite correlations between histone methyltransferase (HMT) activity and gene regulation, direct evidence that HMT activity is responsible for gene activation is sparse. We address the role of the HMT activity for MLL1, a histone H3 lysine 4 (H3K4) methyltransferase critical for maintaining hematopoietic stem cells (HSCs). Here we show that the SET domain and thus HMT activity of MLL1 is dispensable for maintaining HSCs and for supporting leukemogenesis driven by the MLL-AF9 fusion oncoprotein. Upon Mll1 deletion, histone H4 lysine 16 (H4K16) acetylation was selectively depleted at MLL1 target genes in conjunction with reduced transcription. Surprisingly, inhibition of SIRT1 was sufficient to prevent the loss of H4K16 acetylation and the reduction in MLL1 target gene expression. Thus, recruited MOF activity, and not the intrinsic HMT activity of MLL1, is central for the maintenance of HSC target genes. In addition, this work reveals a role for SIRT1 in opposing MLL1 function. 11 Samples, 5 controls and 5 KOs with antibodies H3K4me1, H3K4me3, and H3K27Ac. One input Sample.

2014-04-03 | E-GEOD-56456 | biostudies-arrayexpress

The role of MLL1 in post natal myogenesis

Project description:The trithorax H3K4 histone methyltransferase (HMT) MLL1 has important roles for early embryonic development, hematopoiesis and neurogenesis through regulation of Hox and homeodomain factor expression. MLL1 has been previously implicated in activation of Myf5 expression through an interaction with Pax7. Here, we find that in vivo, MLL1 is necessary for efficient muscle regeneration, and for maintenance of muscle stem and progenitor cells. Loss of MLL1 in cultured myoblasts reveals an essential role for proliferation and expression of both Myf5 and Pax7. Loss of Myf5 is conditional on loss of Pax7 and exogenous Pax7 rescues Myf5 in the absence of MLL1 suggesting a role for MLL1 in Pax7 expression but not Pax7 activity. Importantly, Mll1 knockout results in a minor decrease to H3K4me3 at Pax7, a 40% decrease in Pax7 mRNA and an 85% decrease in Pax7 protein, suggesting a previously proposed non-HMT role for MLL1 may involve linking transcription to translation.

2019-08-16 | GSE108339 | GEO

KDM2B is a Histone H3K79 Demethylase and Induces Transcriptional Repression via SIRT1-mediated Chromatin Silencing

Project description:The methylation of histone H3 lysine 79 (H3K79) acts as an active chromatin marker and is enriched in actively transcribed regions of the genome. However, demethylase of this mark remains unknown despite intensive research. Here, we show that KDM2B (FBXL10), a member of the Jumonji C (JmjC) family of proteins and previously known for its histone H3K36 demethylase activity, is a di- and trimethyl H3K79 demethylase. We demonstrate that KDM2B induces transcriptional repression of HOXA7 and MEIS1 via occupancy of promoters and demethylation of H3K79. Furthermore, genome-wide analysis suggests that H3K79 methylation levels are increased when KDM2B is depleted, suggesting that KDM2B functions as an H3K79 demethylase in vivo. Finally, stable KDM2B-knockdown cell lines exhibited displacement of SIRT1, with concomitant increases in H3K79 methylation and H4K16 acetylation. Our findings identify KDM2B as an H3K79 demethylase and link its function to transcriptional repression via SIRT1-mediated chromatin silencing.

2017-10-21 | GSE89052 | GEO

The NAD+-Dependent SIRT1 Deacetylase Translates a Metabolic Switch into Regulatory Epigenetics in Skeletal Muscle Stem Cells

Project description:Selective genetic ablation of the SIRT1 deacetylase domain in skeletal muscle results in increased H4K16 acetylation and deregulated activation of the myogenic program in satellite cells To establish the role of the deacetylase SIRT1 in skeletal muscle we examined the genome wide distribution of H4K16ac in quiescent (FI) and proliferating (Cul) satellite cells isolated from WT mice (C57Bl/6 background) and SIRT1mKO (generated via breeding of Pax7cre/+ knock-in mice with mice containing the floxed exon 4 SIRT1 allele). We also analyzed the distribution of SIRT1 in quiescent and proliferating FACS isolated WT satellite cells (two replicates). We generated the mRNA profiles (at least two replicate for each experiment) of FACS isolated quiescent, proliferating and differentiating (1 day in differentiation medium) satellite cells of WT mice and SIRT1mKO. The selective genetic ablation of the SIRT1 deacetylase domain in skeletal muscle results in increased H4K16 acetylation and deregulated activation of the myogenic program.

2015-01-30 | E-GEOD-64379 | biostudies-arrayexpress

A structural role for histone methyltransferase MET-2 represses transcription independent of H3K9me catalysis [RNA-seq]

Project description:Packaging genomic regions into silenced heterochromatin is critical to maintain organismal viability and tissue identity. Methylation of histone H3 on lysine 9 (H3K9me) marks heterochromatin. Here we show that in addition to catalyzing H3K9me, the C. elegans histone methyltransferase MET-2 (SETDB1-like) has a second non-catalytic function that can itself contribute to gene repression. We find that subnuclear concentrates, or foci, of MET-2 correlate with efficient HMT activity, yet foci composed of catalytic-deficient MET-2 are also able to mediate transcriptional silencing. Genetic ablation of met-2 or physiological disruption of MET-2 foci by heat stress results in loss of silencing coincident with an increase in histone acetylation. Restoration of catalytically deficient MET-2 foci mitigates H3K9 and H3K27 hyperacetylation, gene derepression, and infertility, demonstrating a structural role for foci of a conserved heterochromatic histone methyltransferase in gene silencing independent of its enzymatic activity.

2021-08-01 | GSE168924 | GEO

A structural role for histone methyltransferase MET-2 represses transcription independent of H3K9me catalysis [ChIP-seq]

2021-08-01 | GSE168923 | GEO

The NAD+-Dependent SIRT1 Deacetylase Translates a Metabolic Switch into Regulatory Epigenetics in Skeletal Muscle Stem Cells

2015-01-30 | GSE64379 | GEO

Global analysis of H3K4 methylation

Project description:This SuperSeries is composed of the following subset Series: GSE18261: Expression analysis on Mll1+/+ and Mll1-/- MEFs GSE18262: ChIP-chip with antibodies for histone 3 lysine 4 trimethylation and histone 3 in Mll1+/+ and Mll1-/- MEFs GSE18263: ChIP-chip with antibodies for histone 3 lysine 4 trimethylation in Mll3+/+ and Mll3-/- MEFs and Ptip+/+ and Ptip-/- MEFs GSE18264: ChIP-chip with antibodies for histone 3 lysine 4 trimethylation, histone 3, and PolII in Mll1+/+ and Mll1-/- MEFs Refer to individual Series

2009-10-20 | E-GEOD-18258 | biostudies-arrayexpress

Histone H3K9 Methyltransferase G9a Represses PPAR? Expression and Adipogenesis [ChIP-Seq and RNA-Seq data]

Project description:PPAR? promotes adipogenesis while Wnt proteins inhibit adipogenesis. However, the mechanisms that control expression of these positive and negative master regulators of adipogenesis remain incompletely understood. By genome-wide histone methylation profiling in preadipocytes, we find that among gene loci encoding adipogenesis regulators, histone methyltransferase (HMT) G9a-mediated repressive epigenetic mark H3K9me2 is enriched on the entire PPAR? locus. H3K9me2 and G9a levels decrease during adipogenesis, which correlates inversely with induction of PPAR?. Removal of H3K9me2 by G9a deletion enhances chromatin opening and binding of adipogenic transcription factor C/EBP-beta to PPAR? promoter, which promotes PPAR? expression. Interestingly, G9a represses PPAR? expression in an HMT activity-dependent manner but facilitates Wnt10a expression independent of its enzymatic activity. Consistently, deletion of G9a or inhibiting G9a HMT activity promotes adipogenesis. Finally, deletion of G9a in mouse adipose tissues increases adipogenic gene expression and tissue weight. Thus, by inhibiting PPAR? expression and facilitating Wnt10a expression, G9a represses adipogenesis. Examination of 3 different histone modification changes in 3T3-L1 preadipocytes

2013-02-01 | E-GEOD-41455 | biostudies-arrayexpress

Enhancer-associated H3K4 mono-methylation by Drosophila Trithorax-related, the Drosophila homolog of Mll3/Mll4

Project description:Mono-methylation of histone H3 on lysine 4 (H3K4me1) and acetylation of histone H3 on lysine 27 (H3K27ac) are histone modifications that are highly enriched over the body of actively transcribed genes and enhancers. Although in yeast all H3K4 methylation patterns including H3K4me1 are implemented by Set1/COMPASS, there are three classes of COMPASS-like complexes in Drosophila that could carry out H3K4me1 on enhancers: dSet1, Trithorax and Trithorax-related (Trr). Here, we report that Trr, the Drosophila homolog of mammalian Mll3/4, can function as a major H3K4 mono-methyltransferase on enhancers in vivo. Loss of Trr results in a global decrease of H3K4me1 and H3K27ac in various tissues. Assays with the cut wing margin enhancer imply a functional role for Trr in enhancer-mediated processes. A genome-wide analysis demonstrates that Trr is required for H3K4me1 and H3K27ac on chromatin signatures that resemble the histone modification patterns described for enhancers. Since Trr and mammalian Mll3/4 complexes are distinguished by bearing a unique subunit, the H3K27 demethylase UTX, we propose a model in which the H3K4 mono-methyltransferase Trr, and the H3K27 demethylase, UTX, cooperate to regulate the transition from inactive/poised to active enhancers. ChIP-seq of Trr, LPT, UTX in Drosophila S2 Cells. ChIP-seq of H3K4me1, H3K4me3, H3K27ac, H3K27me3 in WT and Trr knock-down Drosophila S2 cells. ChIP-seq of H3K4me1, H3K27me3 in LPT knock-down Drosophila S2 cells. ChIP-seq of LPT and UTX in Trr knock-down Drosophila S2 cells. ChIP-seq of H3K4me1 and H3K27me3 in MLL1(+/+), MLL1(-/-), MLL3(+/+), and MLL3(-/-) Mouse Embryonic Fibroblasts (MEFs).

2012-12-01 | E-GEOD-41440 | biostudies-arrayexpress

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