Showing papers by "Hediye Erdjument-Bromage published in 2007"
TL;DR: DNMT3L recognizes histone H3 tails that are unmethylated at lysine 4 and induces de novo DNA methylation by recruitment or activation of DNMT3A2, and substitution of key residues in the binding site eliminated the H3 tail–DN MT3L interaction.
Abstract: Mammals use DNA methylation for the heritable silencing of retrotransposons and imprinted genes and for the inactivation of the X chromosome in females. The establishment of patterns of DNA methylation during gametogenesis depends in part on DNMT3L, an enzymatically inactive regulatory factor that is related in sequence to the DNA methyltransferases DNMT3A and DNMT3B1,2. The main proteins that interact in vivo with the product of an epitope-tagged allele of the endogenous Dnmt3L gene were identified by mass spectrometry as DNMT3A2, DNMT3B and the four core histones. Peptide interaction assays showed that DNMT3L specifically interacts with the extreme amino terminus of histone H3; this interaction was strongly inhibited by methylation at lysine 4 of histone H3 but was insensitive to modifications at other positions. Crystallographic studies of human DNMT3L showed that the protein has a carboxy-terminal methyltransferase-like domain and an N-terminal cysteine-rich domain. Cocrystallization of DNMT3L with the tail of histone H3 revealed that the tail bound to the cysteine-rich domain of DNMT3L, and substitution of key residues in the binding site eliminated the H3 tail-DNMT3L interaction. These data indicate that DNMT3L recognizes histone H3 tails that are unmethylated at lysine 4 and induces de novo DNA methylation by recruitment or activation of DNMT3A2.
1,450 citations
TL;DR: It is shown that nuclear PTEN is essential for tumor suppression and that PTEN nuclear import is mediated by its monoubiquitination, and how a discrete molecular mechanism dictates tumor progression by differentiating between degradation and protection ofPTEN is demonstrated.
716 citations
TL;DR: It is shown that PTEN level is regulated by ubiquitin-mediated proteasomal degradation, and purified its ubiquitIn ligase as HECT-domain protein NEDD4-1, a potential proto-oncogene that negatively regulates PTEN via ubiquitination, a paradigm analogous to that of Mdm2 and p53.
659 citations
TL;DR: It is suggested that methylated H3K4 serves to facilitate the competency of pre-mRNA maturation through the bridging of spliceosomal components to H3k4me3 via CHD1.
562 citations
TL;DR: PLU-1, a transcriptional repressor implicated in breast cancer, is identified as a histone demethylase enzyme that has the ability to reverse the trimethyl H3K4 modification state and is revealed to play an important role in the proliferation capacity of breast cancer cells through repression of tumor suppressor genes, including BRCA1.
474 citations
TL;DR: It is reported that RBP2 is a demethylase that specifically catalyzes demethylation on H3K4, whose methylation is normally associated with transcriptionally active genes, and the first example of a mammalian enzyme capable of erasing trimethylated H 3K4 is provided.
426 citations
TL;DR: A functional link is demonstrated between the heterochromatin-related histone methyltransferase SUV39H1 and the histone deacetylase SIRT1, and these activities independently contribute to elevated levels of SUV39h1 activity resulting in increased levels of the H3K9me3 modification.
Abstract: In contrast to stably repressive, constitutive heterochromatin and stably active, euchromatin, facultative heterochromatin has the capacity to alternate between repressive and activated states of transcription. As such, it is an instructive source to understand the molecular basis for changes in chromatin structure that correlate with transcriptional status. Sirtuin 1 (SIRT1) and suppressor of variegation 3-9 homologue 1 (SUV39H1) are amongst the enzymes responsible for chromatin modulations associated with facultative heterochromatin formation. SUV39H1 is the principal enzyme responsible for the accumulation of histone H3 containing a tri-methyl group at its lysine 9 position (H3K9me3) in regions of heterochromatin. SIRT1 is an NAD+-dependent deacetylase that targets histone H4 at lysine 16 (refs 3 and 4), and through an unknown mechanism facilitates increased levels of H3K9me3 (ref. 3). Here we show that the mammalian histone methyltransferase SUV39H1 is itself targeted by the histone deacetylase SIRT1 and that SUV39H1 activity is regulated by acetylation at lysine residue 266 in its catalytic SET domain. SIRT1 interacts directly with, recruits and deacetylates SUV39H1, and these activities independently contribute to elevated levels of SUV39H1 activity resulting in increased levels of the H3K9me3 modification. Loss of SIRT1 greatly affects SUV39H1-dependent H3K9me3 and impairs localization of heterochromatin protein 1. These findings demonstrate a functional link between the heterochromatin-related histone methyltransferase SUV39H1 and the histone deacetylase SIRT1.
397 citations
TL;DR: It is demonstrated that the malignant-brain-tumor protein L3MBTL1 is in a complex with core histones, histone H1b, HP1gamma, and Rb, and the MBT domain is structurally related to protein domains that directly bind methylated histone residues.
335 citations
TL;DR: It is demonstrated that H2A deubiquitinase is critically involved in cell cycle progression and gene expression and that blocking the function of Ubp-M results in defective posterior development in Xenopus laevis.
Abstract: An enzyme, Ubp-M, is identified that removes the ubiquitin modification from histone H2A. Depletion of Ubp-M leads to slower cell growth and abnormal chromosome segregation in mitosis. In addition, depletion of Ubp-M causes defects in development and dysregulation of Hox gene expression. Post-translational histone modifications have important regulatory roles in chromatin structure and function1,2,3. One example of such modifications is histone ubiquitination, which occurs predominately on histone H2A and H2B. Although the recent identification of the ubiquitin ligase for histone H2A has revealed important roles for H2A ubiquitination in Hox gene silencing4,5,6 as well as in X-chromosome inactivation7,8, the enzyme(s) involved in H2A deubiquitination and the function of H2A deubiquitination are not known. Here we report the identification and functional characterization of the major deubiquitinase for histone H2A, Ubp-M (also called USP16). Ubp-M prefers nucleosomal substrates in vitro, and specifically deubiquitinates histone H2A but not H2B in vitro and in vivo. Notably, knockdown of Ubp-M in HeLa cells results in slow cell growth rates owing to defects in the mitotic phase of the cell cycle. Further studies reveal that H2A deubiquitination by Ubp-M is a prerequisite for subsequent phosphorylation of Ser 10 of H3 and chromosome segregation when cells enter mitosis. Furthermore, we demonstrate that Ubp-M regulates Hox gene expression through H2A deubiquitination and that blocking the function of Ubp-M results in defective posterior development in Xenopus laevis. This study identifies the major deubiquitinase for histone H2A and demonstrates that H2A deubiquitination is critically involved in cell cycle progression and gene expression.
302 citations
TL;DR: The identification of a JAMM/MPN(+) domain-containing histone H2A deubiquitinase specific for monoubiquitinated H 2A (uH2A) that has permitted delineation of a strategy for specific regulatory pathways of gene activation is reported.
274 citations
TL;DR: It is shown that MTERF3 is a negative regulator of mtDNA transcription initiation, the first example of a mitochondrial protein that acts as a specific repressor of mammalian mt DNA transcription initiation in vivo.
TL;DR: Ch Chromatin immunoprecipitation experiments demonstrate that loss of H2B ubiquitylation alters the distribution of polII and histones in gene coding regions and gene expression microarray analysis reveals a greater role for H2 B ubiquitylated in gene regulation than for H3 Lys 4 methylation.
Abstract: Transcription by RNA polymerase II (polII) is accompanied by dramatic changes in chromatin structure. Numerous enzymatic activities contribute to these changes, including ATP-dependent nucleosome remodeling enzymes and histone modifying enzymes. Recent studies in budding yeast document a histone modification pathway associated with polII transcription, whereby ubiquitylation of histone H2B leads to methylation of histone H3 on specific lysine residues. Although this series of events appears to be highly conserved among eukaryotes, its mechanistic function in transcription is unknown. Here we document a significant functional divergence between ubiquitylation of H2B and methylation of Lys 4 on histone H3 in the fission yeast Schizosaccharomyces pombe. Loss of H2B ubiquitylation results in defects in cell growth, septation, and nuclear structure, phenotypes not observed in cells lacking H3 Lys 4 methylation. Consistent with these results, gene expression microarray analysis reveals a greater role for H2B ubiquitylation in gene regulation than for H3 Lys 4 methylation. Chromatin immunoprecipitation (ChIP) experiments demonstrate that loss of H2B ubiquitylation alters the distribution of polII and histones in gene coding regions. We propose that ubiquitylation of H2B impacts transcription elongation and nuclear architecture through its effects on chromatin dynamics.
TL;DR: Drosophila melanogaster protein 'little imaginal discs' (Lid), a JmjC domain–containing trithorax group protein, can demethylate H3K4me3, and positively regulates Hox gene expression in S2 cells.
Abstract: Recent studies have demonstrated that histone methylation can be dynamically regulated through active demethylation. However, no demethylase specific to histone H3 trimethyl-Lys4 (H3K4me3) has been identified. Here we report that the Drosophila melanogaster protein 'little imaginal discs' (Lid), a JmjC domain-containing trithorax group protein, can demethylate H3K4me3. Consistent with its genetic classification, Lid positively regulates Hox gene expression in S2 cells.
TL;DR: Proteomic analysis of endothelial cell (EC) caveolae/lipid raft microdomains is used to report novel biological activities for myoferlin and reveal the role of membrane integrity to VEGF signaling.
TL;DR: The capacity of Rph1 to demethylate H3K9 provides the first indication that S. cerevisiae may have once encoded an H3k9 methylation system and suggests that Rph 1 is a functional vestige of this modification system.
Abstract: Histone methylation is an important posttranslational modification that contributes to chromatin-based processes including transcriptional regulation, DNA repair, and epigenetic inheritance. In the budding yeast Saccharomyces cerevisiae, histone lysine methylation occurs on histone H3 lysines 4, 36, and 79, and its deposition is coupled mainly to transcription. Until recently, histone methylation was considered to be irreversible, but the identification of histone demethylase enzymes has revealed that this modification can be dynamically regulated. In budding yeast, there are five proteins that contain the JmjC domain, a signature motif found in a large family of histone demethylases spanning many organisms. One JmjC-domain-containing protein in budding yeast, Jhd1, has recently been identified as being a histone demethylase that targets H3K36 modified in the di- and monomethyl state. Here, we identify a second JmjC-domain-containing histone demethylase, Rph1, which can specifically demethylate H3K36 tri- and dimethyl modification states. Surprisingly, Rph1 can remove H3K9 methylation, a histone modification not found in budding yeast chromatin. The capacity of Rph1 to demethylate H3K9 provides the first indication that S. cerevisiae may have once encoded an H3K9 methylation system and suggests that Rph1 is a functional vestige of this modification system.
TL;DR: The basis for this remarkable coupling was uncovered: an Rsp5 (E3) dimer assembled on the RNAPII C-terminal domain (CTD), which in turn binds Rsp 5 to allow modification.
TL;DR: Results indicated that DNA-PK promotes the establishment of a repressive chromatin at a TR target promoter by enhancing the HDAC activity of the receptor-bound NCoR/SMRT corepressor complex.
TL;DR: A four-protein nucleosome-binding complex from Schizosaccharomyces pombe, termed SAPHIRE, that includes two orthologs of human Lsd1, a histone demethylase is characterized, suggesting that SAPHIre has both an important enzymatic function and an essential nonenzymatic functions.
Abstract: In this study, we characterize a four-protein nucleosome-binding complex from Schizosaccharomyces pombe, termed SAPHIRE, that includes two orthologs of human Lsd1, a histone demethylase. The SAPHIRE complex is essential for cell viability, whereas saphire mutants lacking key conserved catalytic residues are viable but thermosensitive, suggesting that SAPHIRE has both an important enzymatic function and an essential nonenzymatic function. SAPHIRE is present in (or adjacent to) particular heterochromatic loci and also in the transcription start site regions of many highly active polymerase II genes. However, ribosomal protein genes are notably SAPHIRE deficient. SAPHIRE promotes activation, as target genes are selectively attenuated in saphire mutants. Interestingly, saphire mutants display increased histone H3 lysine 4 dimethylation, a modification typically associated with euchromatin. SAPHIRE localization is dynamic, as activated genes rapidly acquire SAPHIRE. Furthermore, saphire mutants dramatically shift a heterochromatin-euchromatin boundary in Chr1, suggesting a novel role in boundary regulation.
Journal Article•
01 Jan 2007
TL;DR: In this paper, the authors explored the cofactors that interact with the transcriptionallyrepressive form of thyroid hormone receptor (TR) and identified polypep-tide components by mass spectrometry.
Abstract: It is well documented that unliganded thyroid hormonereceptor(TR)functionsasatranscriptionalrepressorofspecificcellular target genes by acting in concert with a corepressorcomplex harboring histone deacetylase (HDAC) activity. Tofully explore the cofactors that interact with the transcription-allyrepressiveformofTR,webiochemicallyisolatedamultipro-teincomplexthatassemblesonaTRretinoidXreceptor(RXR)heterodimerinHeLanuclearextractsandidentifieditspolypep-tide components by mass spectrometry. A subset of TRRXR-associated polypeptides included NCoR, SMRT, TBL1, andHDAC3, which represent the core components of a previouslydescribed NCoR/SMRT corepressor complex. We also identi-fiedseveralpolypeptidesthatconstituteaDNA-dependentpro-tein kinase (DNA-PK) enzyme complex, a regulator of DNArepair, recombination, and transcription. These polypeptidesincluded the catalytic subunit DNA-PKcs, the regulatory sub-units Ku70 and Ku86, and the poly(ADP-ribose) polymerase 1.Densitygradientfractionationandimmunoprecipitationanaly-ses provided evidence for the existence of a high molecularweight TRRXRcorepressor holocomplex containing bothNCoR/SMRT and DNA-PK complexes. Chromatin immuno-precipitation studies confirmed that unliganded TRRXRrecruits both complexes to the triiodothyronine-responsiveregion of growth hormone gene