scholarly journals MYC Interacts with the G9a Histone Methyltransferase to Drive Transcriptional Repression and Tumorigenesis

Cancer Cell ◽  
2018 ◽  
Vol 34 (4) ◽  
pp. 579-595.e8 ◽  
Author(s):  
William B. Tu ◽  
Yu-Jia Shiah ◽  
Corey Lourenco ◽  
Peter J. Mullen ◽  
Dharmendra Dingar ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Histone Methyltransferase

scholarly journals Dynamic Regulation of Histone Modifications in Xenopus Oocytes through Histone Exchange

2006 ◽  
Vol 26 (18) ◽  
pp. 6890-6901 ◽  
Author(s):  
M. David Stewart ◽  
John Sommerville ◽  
Jiemin Wong
Keyword(s):  
Transcriptional Repression ◽  
Xenopus Oocytes ◽  
Transcriptional Activity ◽  
Trichostatin A ◽  
Epigenetic Inheritance ◽  
Histone Methyltransferase ◽  
H3k9 Methylation ◽  
Dynamic Regulation ◽  
Dynamic Exchange ◽  
Histone Exchange

ABSTRACT Histone H3 lysine 9 (H3K9) methylation has broad roles in transcriptional repression, gene silencing, maintenance of heterochromatin, and epigenetic inheritance of heterochromatin. Using Xenopus laevis oocytes, we have previously shown that targeting G9a, an H3K9 histone methyltransferase, to chromatin increases H3K9 methylation and consequently represses transcription. Here we report that treatment with trichostatin A induces histone acetylation and is sufficient to activate transcription repressed by G9a, and this activation is accompanied by a reduction in dimethyl H3K9 (H3K9me2). We tested the possibility that the reduction in H3K9me2 was due to the replacement of methylated H3 with unmethylated H3.3. Surprisingly, we found that both free H3 and H3.3 are continually exchanged with chromatin-associated histones. This dynamic exchange of chromatin-associated H3 with free H3/H3.3 was not affected by alterations in transcriptional activity, elongation, acetylation, H3K9 methylation, or DNA replication. In support of this continual histone exchange model, we show that maintenance of H3K9 methylation at a specific site requires the continual presence of an H3K9 histone methyltransferase. Upon dissociation of the methyltransferase, H3K9 methylation decreases. Taken together, our data suggest that chromatin-associated and non-chromatin-associated histones are continually exchanged in the Xenopus oocyte, creating a highly dynamic chromatin environment.

PU.1 and pRb Bind GATA-1 on DNA and Recruit a Histone H3K9 Methyl Transferase-Containing Complex to Repress the Erythroid Transcription Program.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1614-1614
Author(s):  
Tomas Stopka ◽  
Derek F. Amanatullah ◽  
Arthur I. Skoultchi
Keyword(s):  
Transcriptional Activation ◽  
Binding Sites ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Erythroid Differentiation ◽  
Hematologic Malignancies ◽  
Histone Methyltransferase ◽  
Methyl Transferase ◽  
Cassette Exchange ◽  
Alpha Globin

Abstract Current work indicates that transcriptional repression is at least as important as transcriptional activation in normal development. Inappropriate or untimely transcriptional repression in immature hematopoietic cells is often the basis for a block to differentiation in hematologic malignancies. Activation of PU.1, a myeloid and B-cell specific transcription factor, in erythroid cells plays a key role in Friend virus-induced mouse erythroleukemia (MEL). Previous results from our laboratory showed that PU.1 blocks the erythroid differentiation-promoting activity of GATA-1 by binding directly to GATA-1 on DNA and inhibiting its transcriptional function. PU.1-mediated repression of GATA-1 on transiently transfected GATA-1 target genes is dependent on the corepressor pRb that also binds to PU.1 (Rekhtman et al., Genes & Dev 1999 and Mol Cell Biol 2003). To further investigate the mechanism of PU.1-mediated repression of GATA-1 in chromatin, we examined the occupancy of several GATA-1 target genes by PU.1 and pRb, as well as the state of core histone modifications at these loci in MEL cells by quantitative chromatin immunoprecipitation. These studies included both endogenous GATA-1 target genes and an exogenous GATA-1 target gene (alpha globin) integrated at a specific locus in MEL cells by Recombinase-Mediated Cassette Exchange. We found that GATA-1 sites at both the exogenous, integrated gene as well as at endogenous genes (including the regulatory regions of the alpha globin, beta globin, alas-e, eklf, p45 nf-e2) are occupied by a GATA1 - PU.1 - pRb complex in undifferentiated MEL cells. The presence of all three components of the complex is dependent on intact GATA-1 binding sites in the exogenous, integrated gene. The histone methyltransferase Suv39H1 and the histone H3MeK9 binding protein, HP1alpha, are also present at the repressed loci. During induced differentiation of MEL cells, PU.1, pRb, Suv39H1 and HP1alpha occupancy at these sites declines but GATA-1 continues to be present at its binding sites. The disruption of the repression complex at these loci during differentiation as well as during siRNA-mediated PU.1 knock down is associated with conversion of methylated H3K9 to acetylated H3K9 and significant transcriptional derepression of these GATA-1 target genes. These findings support a model for repression of GATA-1 by PU.1 at endogenous loci through recruitment of the corepressor pRb and associated histone methyltransferase (Suv39H1) and H3MeK9 binding (HP1alpha) activities.

scholarly journals Transcriptional Repression by the Retinoblastoma Protein through the Recruitment of a Histone Methyltransferase

2001 ◽  
Vol 21 (19) ◽  
pp. 6484-6494 ◽  
Author(s):  
Laurence Vandel ◽  
Estelle Nicolas ◽  
Olivier Vaute ◽  
Roger Ferreira ◽  
Slimane Ait-Si-Ali ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Histone H3 ◽  
Histone Methyltransferase ◽  
S Phase ◽  
E2f Transcription Factor ◽  
Cycle Dependent

ABSTRACT The E2F transcription factor controls the cell cycle-dependent expression of many S-phase-specific genes. Transcriptional repression of these genes in G0 and at the beginning of G1by the retinoblasma protein Rb is crucial for the proper control of cell proliferation. Rb has been proposed to function, at least in part, through the recruitment of histone deacetylases. However, recent results indicate that other chromatin-modifying enzymes are likely to be involved. Here, we show that Rb also interacts with a histone methyltransferase, which specifically methylates K9 of histone H3. The results of coimmunoprecipitation experiments of endogenous or transfected proteins indicate that this histone methyltransferase is the recently described heterochromatin-associated protein Suv39H1. Interestingly, phosphorylation of Rb in vitro as well as in vivo abolished the Rb-Suv39H1 interaction. We also found that Suv39H1 and Rb cooperate to repress E2F activity and that Suv39H1 could be recruited to E2F1 through its interaction with Rb. Taken together, these data indicate that Suv39H1 is involved in transcriptional repression by Rb and suggest an unexpected link between E2F regulation and heterochromatin.

scholarly journals Regulation of histone methylation by automethylation of PRC2

2018 ◽  
Author(s):  
Xueyin Wang ◽  
Yicheng Long ◽  
Richard D. Paucek ◽  
Anne R. Gooding ◽  
Thomas Lee ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Histone Methyltransferase ◽  
Post Translational Modification ◽  
Methyltransferase Activity ◽  
Polycomb Repressive Complex 2 ◽  
H3k27 Methylation ◽  
Flexible Loop ◽  
Lysine Residues ◽  
In Cis ◽  
Pseudosubstrate Sequence

ABSTRACTPolycomb Repressive Complex 2 (PRC2) is a histone methyltransferase whose function is critical for regulating transcriptional repression in many eukaryotes including humans. Its catalytic moiety EZH2 is responsible for the tri-methylation of H3K27 and also undergoes automethylation. Using mass spectroscopic analysis of recombinant human PRC2, we identified three methylated lysine residues (K510, K514, K515) on a disordered but highly conserved loop of EZH2. These lysines were mostly mono- and di-methylated. Either mutation of these lysines or their methylation increases PRC2 histone methyltransferase activity. In addition, mutation of these three lysines in HEK293T cells using CRISPR genome-editing increases global H3K27 methylation levels. EZH2 automethylation occurs intramolecularly (in cis) by methylation of a pseudosubstrate sequence on the flexible loop. This post-translational modification andcis-regulation of PRC2 are analogous to the activation of many protein kinases by autophosphorylation. We therefore propose that EZH2 automethylation provides a way for PRC2 to modulate its histone methyltransferase activity by sensing histone H3 tails, SAM concentration, and perhaps other effectors.

scholarly journals An ERG (ets-related gene)-associated histone methyltransferase interacts with histone deacetylases 1/2 and transcription co-repressors mSin3A/B

2003 ◽  
Vol 369 (3) ◽  
pp. 651-657 ◽  
Author(s):  
Liu YANG ◽  
Qi MEI ◽  
Anna ZIELINSKA-KWIATKOWSKA ◽  
Yoshito MATSUI ◽  
Michael L. BLACKBURN ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Histone Methyltransferase ◽  
Luciferase Reporter ◽  
Related Gene ◽  
Luciferase Reporter Gene ◽  
Histone Tails ◽  
Histone Deacetylase 1 ◽  
Covalent Modifications

Covalent modifications of histone tails play important roles in gene transcription and silencing. We recently identified an ERG (ets-related gene)-associated protein with a SET (suppressor of variegation, enhancer of zest and trithorax) domain (ESET) that was found to have the activity of a histone H3-specific methyltransferase. In the present study, we investigated the interaction of ESET with other chromatin remodelling factors. We show that ESET histone methyltransferase associates with histone deacetylase 1 (HDAC1) and HDAC2, and that ESET also interacts with the transcription co-repressors mSin3A and mSin3B. Deletion analysis of ESET reveals that an N-terminal region containing a tudor domain is responsible for interaction with mSin3A/B and association with HDAC1/2, and that truncation of ESET enhances its binding to mSin3. When bound to a promoter, ESET represses the transcription of a downstream luciferase reporter gene. This repression by ESET is independent of its histone methyltransferase activity, but correlates with its binding to the mSin3 co-repressors. In addition, the repression can be partially reversed by treatment with the HDAC inhibitor trichostatin A. Taken together, these data suggest that ESET histone methyltransferase can form a large, multi-protein complex(es) with mSin3A/B co-repressors and HDAC1/2 that participates in multiple pathways of transcriptional repression.

scholarly journals The SUMO ligase Su(var)2-10 links piRNA-guided target recognition to chromatin silencing

2019 ◽  
Author(s):  
Maria Ninova ◽  
Yung-Chia Ariel Chen ◽  
Baira Godneeva ◽  
Alicia K. Rogers ◽  
Yicheng Luo ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Target Recognition ◽  
Regulatory Gene ◽  
E3 Ligase ◽  
Histone Methyltransferase ◽  
Regulation Of Transcription ◽  
List Type ◽  
Control Of Gene Expression ◽  
Precise Control ◽  
Sumo E3 Ligase

AbstractRegulation of transcription is the main mechanism responsible for precise control of gene expression. While the majority of transcriptional regulation is mediated by a multitude of DNA-binding transcription factors that bind to regulatory gene regions, an elegant alternative strategy employs small RNA guides, piwi-interacting RNAs (piRNAs) to identify targets of transcriptional repression. Here we show that in Drosophila the small ubiquitin-like protein SUMO and the SUMO E3 ligase Su(var)2-10 are required for piRNA-guided deposition of repressive chromatin marks and transcriptional silencing of piRNA targets. Su(var)2-10 links the piRNA-guided target recognition complex to the silencing effector by binding the piRNA/Piwi complex and inducing SUMO-dependent recruitment of the SetDB1/Wde histone methyltransferase effector. We propose that in Drosophila, the nuclear piRNA pathway has co-opted a conserved mechanism of SUMO-dependent recruitment of the SetDB1/Wde chromatin modifier to confer repression of genomic parasites.Highlights-piRNA-induced transposon silencing requires SUMO and the SUMO E3 ligase Su(var)2-10-Su(var)2-10 links the target recognition complex to the silencing effector-Su(var)2-10 binds the piRNA-guided target recognition complex and deposits SUMO on target chromatin-Su(var)2-10 induces SUMO-dependent recruitment of the SetDB1/Wde histone methyltransferase to target loci

scholarly journals Multiple Myeloma-Related WHSC1/MMSET Isoform RE-IIBP Is a Histone Methyltransferase with Transcriptional Repression Activity

2008 ◽  
Vol 28 (6) ◽  
pp. 2023-2034 ◽  
Author(s):  
Ji-Young Kim ◽  
Hae Jin Kee ◽  
Nak-Won Choe ◽  
Sung-Mi Kim ◽  
Gwang-Hyeon Eom ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Transcriptional Repression ◽  
Histone H3 ◽  
Histone Methyltransferase ◽  
Set Domain ◽  
Interleukin 5 ◽  
Hmtase Activity ◽  
Critical Residues ◽  
Tumor Types

ABSTRACT Histone methylation is crucial for transcriptional regulation and chromatin remodeling. It has been suggested that the SET domain containing protein RE-IIBP (interleukin-5 [IL-5] response element II binding protein) may perform a function in the carcinogenesis of certain tumor types, including myeloma. However, the pathogenic role of RE-IIBP in these diseases remains to be clearly elucidated. In this study, we have conducted an investigation into the relationship between the histone-methylating activity of RE-IIBP and transcriptional regulation. Here, we report that RE-IIBP is up-regulated in the blood cells of leukemia patients, and we characterized the histone H3 lysine 27 (H3-K27) methyltransferase activity of RE-IIBP. Point mutant analysis revealed that SET domain cysteine 483 and arginine 477 are critical residues for the histone methyltransferase (HMTase) activity of RE-IIBP. RE-IIBP also represses basal transcription via histone deacetylase (HDAC) recruitment, which may be mediated by H3-K27 methylation. In the chromatin immunoprecipitation assays, we showed that RE-IIBP overexpression induces histone H3-K27 methylation, HDAC recruitment, and histone H3 hypoacetylation on the IL-5 promoter and represses expression. Conversely, short hairpin RNA-mediated knockdown of RE-IIBP reduces histone H3-K27 methylation and HDAC occupancy around the IL-5 promoter. These data illustrate the important regulatory role of RE-IIBP in transcriptional regulation, thereby pointing to the important role of HMTase activity in carcinogenesis.

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