The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis

Glaser, Stefan; Lubitz, Sandra; Loveland, Kate; Ohbo, Kazu; Robb, Lorraine; Schwenk, Frieder; Seibler, Jost; Roellig, Daniela; Kranz, Andrea; Anastassiadis, Konstantinos; Stewart, A. Francis

doi:10.1186/1756-8935-2-5

Cited by 162 publications

(159 citation statements)

References 58 publications

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“…Although the SET domain/enzymatic activity of several MLL-related proteins have been shown to be critical for gene regulation (Ding et al, 2012;Lee et al, 2006;Tie et al, 2014), recent evidence suggests that MLL1 and MLL2 exhibit very specialized H3K4me activities that are restricted to particular cell types and target genes (Andreu-Vieyra et al, 2010;Austenaa et al, 2012;Glaser et al, 2009;Ladopoulos et al, 2013). Nonetheless, both MLL1 and MLL2 regulate many unique gene expression programs above and beyond genes that are directly H3K4-methylated.…”

Section: Discussionmentioning

confidence: 99%

The histone methyltransferase activity of mll1 is dispensable for hematopoiesis and leukemogenesis

Mishra

Yang

Zaffuto

et al. 2014

Experimental Hematology

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Section: Discussionmentioning

confidence: 99%

The histone methyltransferase activity of mll1 is dispensable for hematopoiesis and leukemogenesis

Mishra

Yang

Zaffuto

et al. 2014

Experimental Hematology

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“…G418-resistant cells from the third plating were transduced with retroviral constructs encoding Bcl-2 family members or RNA hairpins for knockdown of Bim and were linked with IRES-GFP, and transduced cells were subsequently isolated by cell sorting. Cremediated recombination in vitro was induced by treatment with 10 À7 M 4-hydroxy tamoxifen (Sigma, H7904) (Glaser et al 2009). For analysis of protein levels by Western blotting, mcl-1 fl/fl ;creER/+ cells were treated with tamoxifen in the presence of the pan-caspase inhibitor qVD-OPh (25 mM; MP Biomedicals) to protect them from apoptotic death.…”

Section: Animalsmentioning

confidence: 99%

Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia

Glaser¹,

Lee²,

Trounson³

et al. 2012

Genes Dev.

Self Cite

360

351

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Acute myeloid leukemia (AML) frequently relapses after initial treatment. Drug resistance in AML has been attributed to high levels of the anti-apoptotic Bcl-2 family members Bcl-xL and Mcl-1. Here we report that removal of Mcl-1, but not loss or pharmacological blockade of Bcl-xL, Bcl-2, or Bcl-w, caused the death of transformed AML and could cure disease in AML-afflicted mice. Enforced expression of selective inhibitors of prosurvival Bcl-2 family members revealed that Mcl-1 is critical for survival of human AML cells. Thus, targeting of Mcl-1 or regulators of its expression may be a useful strategy for the treatment of AML.

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“…For example, methylation of histone H3-lysine 4, including the trimethylated form (H3K4me3)-sharply enriched at gene-proximal promoters and transcription start sites (TSS; Guenther et al, 2007;Barrera et al, 2008)-is highly regulated throughout all periods of development and aging in the human and nonhuman primate cerebral cortex (Cheung et al, 2010;Han et al, 2012), and altered in a locus-specific manner in cortical neurons of subjects diagnosed with neuropsychiatric (Huang et al, 2007;Shulha et al, 2012) or neurodegenerative (Bai et al, 2015) disease. Furthermore, mutations in at least six human genes encoding H3K4-specific demethylases or methyltransferases (KDM5A, KDM5C, KMT2A, KMT2C, KMT2D, and KMT2F ) have been linked to various neurodevelopmental disorders and syndromes Takata et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Neuronal Kmt2a/Mll1 Histone Methyltransferase Is Essential for Prefrontal Synaptic Plasticity and Working Memory

Jakovcevski

Ruan

Shen³

et al. 2015

J. Neurosci.

133

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Neuronal histone H3-lysine 4 methylation landscapes are defined by sharp peaks at gene promoters and other cis-regulatory sequences, but molecular and cellular phenotypes after neuron-specific deletion of H3K4 methyl-regulators remain largely unexplored. We report that neuronal ablation of the H3K4-specific methyltransferase, Kmt2a/Mixed-lineage leukemia 1 (Mll1), in mouse postnatal forebrain and adult prefrontal cortex (PFC) is associated with increased anxiety and robust cognitive deficits without locomotor dysfunction. In contrast, only mild behavioral phenotypes were observed after ablation of the Mll1 ortholog Kmt2b/Mll2 in PFC. Impaired working memory after Kmt2a/Mll1 ablation in PFC neurons was associated with loss of training-induced transient waves of Arc immediate early gene expression critical for synaptic plasticity. Medial prefrontal layer V pyramidal neurons, a major output relay of the cortex, demonstrated severely impaired synaptic facilitation and temporal summation, two forms of short-term plasticity essential for working memory. Chromatin immunoprecipitation followed by deep sequencing in Mll1-deficient cortical neurons revealed downregulated expression and loss of the transcriptional mark, trimethyl-H3K4, at Ͻ50 loci, including the homeodomain transcription factor Meis2. Small RNAmediated Meis2 knockdown in PFC was associated with working memory defects similar to those elicited by Mll1 deletion. Therefore, mature prefrontal neurons critically depend on maintenance of Mll1-regulated H3K4 methylation at a subset of genes with an essential role in cognition and emotion.

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The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis

Cited by 162 publications

References 58 publications

The histone methyltransferase activity of mll1 is dispensable for hematopoiesis and leukemogenesis

The histone methyltransferase activity of mll1 is dispensable for hematopoiesis and leukemogenesis

Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia

Neuronal Kmt2a/Mll1 Histone Methyltransferase Is Essential for Prefrontal Synaptic Plasticity and Working Memory

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