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  • G9a/GLP histone lysine dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory conso ... 22514307

    Learning triggers alterations in gene transcription in brain regions such as the hippocampus and the entorhinal cortex (EC) that are necessary for long-term memory (LTM) formation. Here, we identify an essential role for the G9a/G9a-like protein (GLP) lysine dimethyltransferase complex and the histone H3 lysine 9 dimethylation (H3K9me2) marks it catalyzes, in the transcriptional regulation of genes in area CA1 of the rat hippocampus and the EC during memory consolidation. Contextual fear learning increased global levels of H3K9me2 in area CA1 and the EC, with observable changes at the Zif268, DNMT3a, BDNF exon IV, and cFOS gene promoters, which occurred in concert with mRNA expression. Inhibition of G9a/GLP in the EC, but not in the hippocampus, enhanced contextual fear conditioning relative to control animals. The inhibition of G9a/GLP in the EC induced several histone modifications that include not only methylation but also acetylation. Surprisingly, we found that downregulation of G9a/GLP activity in the EC enhanced H3K9me2 in area CA1, resulting in transcriptional silencing of the non-memory permissive gene COMT in the hippocampus. In addition, synaptic plasticity studies at two distinct EC-CA1 cellular pathways revealed that G9a/GLP activity is critical for hippocampus-dependent long-term potentiation initiated in the EC via the perforant pathway, but not the temporoammonic pathway. Together, these data demonstrate that G9a/GLP differentially regulates gene transcription in the hippocampus and the EC during memory consolidation. Furthermore, these findings support the possibility of a role for G9a/GLP in the regulation of cellular and molecular cross talk between these two brain regions during LTM formation.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription. 18818694

    Methylation of DNA and lysine 9 of histone H3 (H3K9) are well-conserved epigenetic marks for transcriptional silencing. Although H3K9 methylation directs DNA methylation in filamentous fungi and plants, this pathway has not been corroborated in mammals. G9a and GLP/Eu-HMTase1 are two-related mammalian lysine methyltransferases and a G9a/GLP heteromeric complex regulates H3K9 methylation of euchromatin. To elucidate the function of G9a/GLP-mediated H3K9 methylation in the regulation of DNA methylation and transcriptional silencing, we characterized ES cells expressing catalytically inactive mutants of G9a and/or GLP. Interestingly, in ES cells expressing a G9a-mutant/GLP complex that does not rescue global H3K9 methylation, G9a/GLP-target genes remain silent. The CpG sites of the promoter regions of these genes were hypermethylated in such mutant ES cells, but hypomethylated in G9a- or GLP-KO ES cells. Treatment with a DNA methyltransferase inhibitor reactivates these G9a/GLP-target genes in ES cells expressing catalytically inactive G9a/GLP proteins, but not the wild-type proteins. This is the first clear evidence that G9a/GLP suppresses transcription by independently inducing both H3K9 and DNA methylation.
    Document Type:
    Reference
    Product Catalog Number:
    07-523
    Product Catalog Name:
    Anti-trimethyl-Histone H3 (Lys9) Antibody

  • LSH and G9a/GLP complex are required for developmentally programmed DNA methylation. 21149390

    LSH, a member of the SNF2 family of chromatin remodeling ATPases encoded by the Hells gene, is essential for normal levels of DNA methylation in the mammalian genome. While the role of LSH in the methylation of repetitive DNA sequences is well characterized, its contribution to the regulation of DNA methylation and the expression of protein-coding genes has not been studied in detail. In this report we investigate genome-wide patterns of DNA methylation at gene promoters in Hells(-/-) mouse embryonic fibroblasts (MEFs). We find that in the absence of LSH, DNA methylation is lost or significantly reduced at ∼20% of all normally methylated promoter sequences. As a consequence, a large number of genes are misexpressed in Hells(-/-) MEFs. Comparison of Hells(-/-) MEFs with wild-type MEFs and embryonic stem (ES) cells suggests that LSH is important for de novo DNA methylation events that accompany the establishment and differentiation of embryonic lineage cells. We further show that the generation of normal DNA methylation patterns and stable gene silencing at specific promoters require cooperation between LSH and the G9a/GLP complex of histone methylases. At such loci, G9a recruitment is compromised when LSH is absent or greatly reduced. Taken together, our data suggest a mechanism whereby LSH promotes binding of DNA methyltransferases and the G9a/GLP complex to specific loci and facilitates developmentally programmed DNA methylation and stable gene silencing during lineage commitment and differentiation.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. 15774718

    Histone H3 Lys 9 (H3-K9) methylation is a crucial epigenetic mark for transcriptional silencing. G9a is the major mammalian H3-K9 methyltransferase that targets euchromatic regions and is essential for murine embryogenesis. There is a single G9a-related methyltransferase in mammals, called GLP/Eu-HMTase1. Here we show that GLP is also important for H3-K9 methylation of mouse euchromatin. GLP-deficiency led to embryonic lethality, a severe reduction of H3-K9 mono- and dimethylation, the induction of Mage-a gene expression, and HP1 relocalization in embryonic stem cells, all of which were phenotypes of G9a-deficiency. Furthermore, we show that G9a and GLP formed a stoichiometric heteromeric complex in a wide variety of cell types. Biochemical analyses revealed that formation of the G9a/GLP complex was dependent on their enzymatic SET domains. Taken together, our new findings revealed that G9a and GLP cooperatively exert H3-K9 methyltransferase function in vivo, likely through the formation of higher-order heteromeric complexes.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Immunoelectron microscopic observation of chicken glucagon-like peptide (GLP)-1-containing cells in tissues derived from thin section, paraffin block and conventional met ... 24257328

    The purpose of the present study was to investigate the possibility of immunoelectron microscopic observation of endocrine cells in paraffin-embedded tissues. The procedure, which involves reprocessing from sliced tissues and immunohistochemical staining by colloidal-gold immunolabeling of paraffin sections from paraffin blocks, was able to reveal the fine characteristics of secretory granules containing glucagon-like peptide-1. Morphometric analyses of the secretory granules showed no significant differences between the reprocessing procedure and a conventional post-embedding procedure, which was performed as a control. The reprocessing procedure has some advantages besides providing information on secretory granules containing the amino acid peptide. For example, the same cell can be observed under both a light microscope and the electron microscope. In addition, the high-electron densities of silver-enhanced gold particles are easily recognized, and the boundary between the profile of the granules and the immunogold labeling is clearly shown at the electron microscopic level. Furthermore, the procedure, which is inexpensive and does not require special devices, can effectively use precious samples that are already paraffin-embedded and unable to be obtained twice, such as the case for endangered animals and rare pathological tissues. To the best of our knowledge, the present study is the first to report the advantages of the reprocessing method for sliced paraffin sections of gut endocrine cells.
    Document Type:
    Reference
    Product Catalog Number:
    AP132B
    Product Catalog Name:
    Goat Anti-Rabbit IgG Antibody, biotin-SP conjugate

  • Involvement of histone methyltransferase GLP in HIV-1 latency through catalysis of H3K9 dimethylation. 23541084

    Understanding the mechanism of HIV-1 latency is crucial to eradication of the viral reservoir in HIV-1-infected individuals. However, the role of histone methyltransferase (HMT) G9a-like protein (GLP) in HIV-1 latency is still unclear. In the present work, we established four clonal cell lines containing HIV-1 vector. We found that the integration sites of most clonal cell lines favored active gene regions. However, we also observed hypomethylation of CpG of HIV 5'LTR in all four clonal cell lines. Additionally, 5'-deoxy-5'-methylthioadenosine (MTA), a broad-spectrum histone methyltransferase inhibitor, was used to examine the role of histone methylation in HIV-1 latency. MTA was found to decrease the level of H3K9 dimethylation, causing reactivation of latent HIV-1 in C11 cells. GLP knockdown by small interfering RNA clearly induced HIV-1 LTR expression. Results suggest that GLP may play a significant role in the maintenance of HIV-1 latency by catalyzing dimethylation of H3K9.
    Document Type:
    Reference
    Product Catalog Number:
    17-371
    Product Catalog Name:
    EZ-ChIP™

  • A subset of the histone H3 lysine 9 methyltransferases Suv39h1, G9a, GLP, and SETDB1 participate in a multimeric complex. 20129054

    Lysine 9 of histone 3 (H3K9) can be mono-, di-, or trimethylated, inducing distinct effects on gene expression and chromatin compaction. H3K9 methylation can be mediated by several histone methyltransferases (HKMTs) that possess mono-, di-, or trimethylation activities. Here we provide evidence that a subset of each of the main H3K9 HKMTs, G9a/KMT1C, GLP/KMT1D, SETDB1/KMT1E, and Suv39h1/KMT1A, coexist in the same megacomplex. Moreover, in Suv39h or G9a null cells, the remaining HKMTs are destabilized at the protein level, indicating that the integrity of these HKMTs is interdependent. The four HKMTs are recruited to major satellite repeats, a known Suv39h1 genomic target, but also to multiple G9a target genes. Moreover, we report a functional cooperation between the four H3K9 HKMTs in the regulation of known G9a target genes. Altogether, our data identify a H3K9 methylation multimeric complex.
    Document Type:
    Reference
    Product Catalog Number:
    07-551
    Product Catalog Name:
    Anti-G9a Antibody

  • Lysine methylation of the NF-κB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-κB signaling. 21131967

    Signaling via the methylation of lysine residues in proteins has been linked to diverse biological and disease processes, yet the catalytic activity and substrate specificity of many human protein lysine methyltransferases (PKMTs) are unknown. We screened over 40 candidate PKMTs and identified SETD6 as a methyltransferase that monomethylated chromatin-associated transcription factor NF-κB subunit RelA at Lys310 (RelAK310me1). SETD6-mediated methylation rendered RelA inert and attenuated RelA-driven transcriptional programs, including inflammatory responses in primary immune cells. RelAK310me1 was recognized by the ankryin repeat of the histone methyltransferase GLP, which under basal conditions promoted a repressed chromatin state at RelA target genes through GLP-mediated methylation of histone H3 Lys9 (H3K9). NF-κB-activation-linked phosphorylation of RelA at Ser311 by protein kinase C-ζ (PKC-ζ) blocked the binding of GLP to RelAK310me1 and relieved repression of the target gene. Our findings establish a previously uncharacterized mechanism by which chromatin signaling regulates inflammation programs.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Nicotine induces chromatin remodelling through decreases in the methyltransferases GLP, G9a, Setdb1 and levels of H3K9me2. 23067581

    Studies examining the epigenetic effects of nicotine are limited, but indicate that nicotine can promote a transcriptionally permissive chromatin environment by increasing acetylation of histone H3 and H4. To further explore nicotine-induced histone modifications, we measured histone methyltransferase (HMT) mRNA expression as well as total and promoter-specific H3K9me2 levels. Following administration of nicotine, HMT mRNA and H3K9me2 levels were examined in mouse primary cortical neuronal culture and cortex extracted from mice injected intraperitoneally, as well as in human lymphocyte culture. Furthermore, Bdnf/BDNF mRNA levels were examined as an epigenetically regulated read-out of gene expression. There was a significant decrease of the HMT GLP, G9a and Setdb1 mRNA expression in the nicotine-treated tissue examined, with significant decreases seen in both total and promoter-specific H3K9me2 levels. Increasing doses of nicotine resulted in significant decreases in Bdnf/BDNF promoter specific H3K9me2 binding, leading to enhanced Bdnf/BDNF transcription. Taken together, our data suggest that nicotine reduces markers of a restrictive epigenomic state, thereby leading to a more permissive epigenomic environment.
    Document Type:
    Reference
    Product Catalog Number:
    05-457
    Product Catalog Name:
    Anti-Histone H1 Antibody, clone AE-4

  • Sodium arsenite represses the expression of myogenin in C2C12 mouse myoblast cells through histone modifications and altered expression of Ezh2, Glp, and Igf-1. 22426358

    Arsenic is a toxicant commonly found in water systems and chronic exposure can result in adverse developmental effects including increased neonatal death, stillbirths, and miscarriages, low birth weight, and altered locomotor activity. Previous studies indicate that 20 nM sodium arsenite exposure to C2C12 mouse myocyte cells delayed myoblast differentiation due to reduced myogenin expression, the transcription factor that differentiates myoblasts into myotubes. In this study, several mechanisms by which arsenic could alter myogenin expression were examined. Exposing differentiating C2C12 cells to 20 nM arsenic increased H3K9 dimethylation (H3K9me2) and H3K9 trimethylation (H3K9me3) by 3-fold near the transcription start site of myogenin, which is indicative of increased repressive marks, and reduced H3K9 acetylation (H3K9Ac) by 0.5-fold, indicative of reduced permissive marks. Protein expression of Glp or Ehmt1, a H3-K9 methyltransferase, was also increased by 1.6-fold in arsenic-exposed cells. In addition to the altered histone remodeling status on the myogenin promoter, protein and mRNA levels of Igf-1, a myogenic growth factor, were significantly repressed by arsenic exposure. Moreover, a 2-fold induction of Ezh2 expression, and an increased recruitment of Ezh2 (3.3-fold) and Dnmt3a (~2-fold) to the myogenin promoter at the transcription start site (-40 to +42), were detected in the arsenic-treated cells. Together, we conclude that the repressed myogenin expression in arsenic-exposed C2C12 cells was likely due to a combination of reduced expression of Igf-1, enhanced nuclear expression and promoter recruitment of Ezh2, and altered histone remodeling status on myogenin promoter (-40 to +42).
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple