mAM Facilitates Conversion by ESET of Dimethyl to Trimethyl Lysine 9 of Histone H3 to Cause Transcriptional Repression

Wang, Hengbin; An, Woojin; Cao, Ran; Li, Xia; Erdjument‐Bromage, Hediye; Chatton, Bruno; Tempst, Paul; Roeder, Robert G.; Zhang, Yi

doi:10.1016/j.molcel.2003.08.007

Cited by 303 publications

(315 citation statements)

References 37 publications

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“…Three methyltransferases G9a, GLP-1 (EuHMTare), and ESET (SetDB1) have been identified to be able to catalyze the formation of H3K9me2 [8,[10][11][12][13], and G9a is a major histone methyltransferase for H3K9me2, because knockout of this gene in mice causes a 90% loss of H3K9me2 [6,7,9].…”

Section: Introductionmentioning

confidence: 99%

PHF8 is a histone H3K9me2 demethylase regulating rRNA synthesis

Zhu

Wang

et al. 2010

Cell Res

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Dimethylation of histone H3 lysine 9 (H3K9me2) is an important epigenetic mark associated with transcription repression. Here, we identified PHF8, a JmjC-domain-containing protein, as a histone demethylase specific for this repressing mark. Recombinant full-length wild type protein could remove methylation from H3K9me2, but mutation of a conserved histidine to alanine H247A abolished the demethylase activity. Overexpressed exogenous PHF8 was colocalized with B23 staining. Endogenous PHF8 was also colocalized with B23 and fibrillarin, two well-established nucleolus proteins, suggesting that PHF8 is localized in the nucleolus and may regulate rRNA transcription. Indeed, PHF8 bound to the promoter region of the rDNA gene. Knockdown of PHF8 reduced the expression of rRNA, and overexpression of the gene resulted in upregulation of rRNA transcript. Concomitantly, H3K9me2 level was elevated in the promoter region of the rDNA gene in PHF8 knockdown cells and reduced significantly when the wild type but not the catalytically inactive H247A mutant PHF8 was overexpressed. Thus, our study identified a histone demethylase for H3K9me2 that regulates rRNA transcription.

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Section: Introductionmentioning

confidence: 99%

PHF8 is a histone H3K9me2 demethylase regulating rRNA synthesis

Zhu

Wang

et al. 2010

Cell Res

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“…We also identified two previously unknown proteins, Pcgf3 and Pcgf5, together with Nspc1/ Pcgf1 (31), which are three RING finger proteins related to the PcG products Bmi1/Pcgf4 and Mel18/Pcgf2. The histone H3 Lys-9 methyltransferase Setdb1, together with its activating partner, mAM (46), was also identified in the analysis, although the sequence coverage of the corresponding peptides was relatively low, possibly indicating non-stoichiometric amounts or a low abundance complex. Another interesting putative new interactor is the ubiquitin protease encoded by the Usp7 gene, which has been shown in flies to interact genetically with PcG genes (47).…”

Section: Resultsmentioning

confidence: 99%

Proteomics Analysis of Ring1B/Rnf2 Interactors Identifies a Novel Complex with the Fbxl10/Jhdm1B Histone Demethylase and the Bcl6 Interacting Corepressor

Sánchez

Demmers³

et al. 2007

Molecular & Cellular Proteomics

208

192

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Ring1B/Rnf2 is a RING finger protein member of the Polycomb group (PcG) of proteins, which form chromatinmodifying complexes essential for embryonic development and stem cell renewal and which are commonly deregulated in cancer. Ring1B/Rnf2 is a ubiquitin E3 ligase that catalyzes the monoubiquitylation of the histone H2A, one of the histone modifications needed for the transcriptional repression activity of the PcG of proteins. Ring1B/Rnf2 was shown to be part of two complexes, the PRC1 PcG complex and the E2F6.com-1 complex, which also contains non-PcG members, thus raising the prospect for additional Ring1B/Rnf2 partners and functions extending beyond the PcG. Here we used a high throughput proteomics approach based on the single step purification, using streptavidin beads, of in vivo biotinylated Ring1B/Rnf2 and associated proteins from a nuclear extract from erythroid cells and their identification by mass spectrometry. About 50 proteins were confidently identified of which 20 had not been identified previously as subunits of Ring1B/Rnf2 complexes. We found that histone demethylases LSD1/Aof2 and Fbxl10/Jhdm1B, casein kinase subunits, and the BcoR corepressor were among the new interactors identified. We also isolated an Fbxl10/Jhdm1B complex by biotinylation tagging to identify shared interacting partners with Ring1B/Rnf2. In this way we identified a novel Ring1B-Fbxl10 complex that also includes Bcl6 corepressor (BcoR), CK2␣, Skp1, and Nspc1/Pcgf1. The putative enzymatic activities and protein interaction and chromatin binding motifs present in this novel Ring1B-Fbxl10 complex potentially provide additional mechanisms for chromatin modification/recruitment to chromatin and more evidence for Ring1B/Rnf2 activities beyond those typically associated with PcG function. Lastly this work demonstrates the utility of biotinylation tagging for the rapid characterization of complex mixtures of multiprotein complexes achieved through the iterative use of this simple yet high throughput proteomics approach.Molecular & Cellular Proteomics 6:820 -834, 2007.In multicellular organisms, cell identity is controlled, at least in part, by epigenetic events, including DNA methylation and post-translational modifications of histones that lead to chromatin structure regulation (1). These modifications are carried out by protein complexes recruited through DNA sequences and/or specific recognition of modified histones. The Polycomb group (PcG) 1 of proteins, first identified genetically as regulators of Hox genes in the fly Drosophila melanogaster (for a review, see Ref. 2), is an example of such a complex. PcG functions cover many aspects of vertebrate development and tissue homeostasis by preventing the inappropriate activation of many transcription factor-coding genes and other genes involved in cell signaling and cell proliferation (3-7). Currently it is believed that PcG proteins play a role in setting the balance between proliferation and differentiation in normal development. Deregulation of PcG proteins disrupts such a ba...

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“…The other type of HMTases methylates histone octamers, but exhibit a low rate of catalysis for nucleosomal histones. Interestingly, all of the characterized H3-K9 HMTases in mammals (i.e., Suv39h, EuHMTase1/GLP, and SETDB1/ESET), belong to the latter group (Ogawa et al 2002;Wang et al 2003;Schotta et al 2004). To assess whether any enzymatic differences existed between the G9/GLP heteromeric complex and G9a or GLP alone, we performed in vitro HMTase assay (Supplementary Fig.…”

Section: G9a and Glp Cooperatively Exert H3-k9 Methyltransferase Funcmentioning

confidence: 99%

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

Tachibana¹,

Ueda²,

Fukuda³

et al. 2005

Genes Dev.

718

760

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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.[Keywords: Histone; methylation; G9a; GLP] Supplemental material is available at http://www.genesdev.org.

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mAM Facilitates Conversion by ESET of Dimethyl to Trimethyl Lysine 9 of Histone H3 to Cause Transcriptional Repression

Cited by 303 publications

References 37 publications

PHF8 is a histone H3K9me2 demethylase regulating rRNA synthesis

PHF8 is a histone H3K9me2 demethylase regulating rRNA synthesis

Proteomics Analysis of Ring1B/Rnf2 Interactors Identifies a Novel Complex with the Fbxl10/Jhdm1B Histone Demethylase and the Bcl6 Interacting Corepressor

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

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