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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

LSD1 is a recently identified human lysine (K)-specific histone demethylase. LSD1 is associated with HDAC1/2; CoREST, a SANT domain-containing corepressor; and BHC80, a PHD domain-containing protein, among others. We show that CoREST endows LSD1 with the ability to demethylate nucleosomal substrates and that it protects LSD1 from proteasomal degradation in vivo. We find hyperacetylated nucleosomes less susceptible to CoREST/LSD1-mediated demethylation, suggesting that hypoacetylated nucleosomes may be the preferred physiological substrates. This raises the possibility that histone deacetylases and LSD1 may collaborate to generate a repressive chromatin environment. Consistent with this model, TSA treatment results in derepression of LSD1 target genes. While CoREST positively regulates LSD1 function, BHC80 inhibits CoREST/LSD1-mediated demethylation in vitro and may therefore confer negative regulation. Taken together, these findings suggest that LSD1-mediated histone demethylation is regulated dynamically in vivo. This is expected to have profound effects on gene expression under both physiological and pathological conditions.
Mol Cell 2005 Sep 16
PMID:Regulation of LSD1 histone demethylase activity by its associated factors. 1614 33

Histone deacetylase (HDAC) inhibitors are a promising class of anticancer agents for the treatment of solid and hematological malignancies. The precise mechanism by which HDAC inhibitors mediate their effects on tumor cell growth, differentiation, and/or apoptosis is the subject of intense research. Previously we described a family of multiprotein complexes that contain histone deacetylase 1/2 (HDAC1/2) and the histone demethylase BHC110 (LSD1). Here we show that HDAC inhibitors diminish histone H3 lysine 4 (H3K4) demethylation by BHC110 in vitro. In vivo analysis revealed an increased H3K4 methylation concomitant with inhibition of nucleosomal deacetylation by HDAC inhibitors. Reconstitution of recombinant complexes revealed a functional connection between HDAC1 and BHC110 only when nucleosomal substrates were used. Importantly, while the enzymatic activity of BHC110 is required to achieve optimal deacetylation in vitro, in vivo analysis following ectopic expression of an enzymatically dead mutant of BHC110 (K661A) confirmed the functional cross talk between the demethylase and deacetylase enzymes. Our studies not only reveal an intimate link between the histone demethylase and deacetylase enzymes but also identify histone demethylation as a secondary target of HDAC inhibitors.
Mol Cell Biol 2006 Sep
PMID:Functional interplay between histone demethylase and deacetylase enzymes. 1691 25

The corepressor BCOR potentiates transcriptional repression by the proto-oncoprotein BCL6 and suppresses the transcriptional activity of a common mixed-lineage leukemia fusion partner, AF9. Mutations in human BCOR cause male lethal, X-linked oculofaciocardiodental syndrome. We identified a BCOR complex containing Polycomb group (PcG) and Skp-Cullin-F-box subcomplexes. The PcG proteins include RING1, RYBP, NSPC1, a Posterior Sex Combs homolog, and RNF2, an E3 ligase for the mono-ubiquitylation of H2A. BCOR complex components and mono-ubiquitylated H2A localize to BCL6 targets, indicating that the BCOR complex employs PcG proteins to expand the repertoire of enzymatic activities that can be recruited by BCL6. This also suggests that BCL6 can target PcG proteins to DNA. In addition, the BCOR complex contains components of a second ubiquitin E3 ligase, namely, SKP1 and FBXL10 (JHDM1B). We show that BCOR coimmunoprecipitates isoforms of FBXL10 which contain a JmjC domain that recently has been determined to have histone H3K36 demethylase activity. The recruitment of two distinct classes of E3 ubiquitin ligases and a histone demethylase by BCOR suggests that BCOR uses a unique combination of epigenetic modifications to direct gene silencing.
Mol Cell Biol 2006 Sep
PMID:Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets. 1694 29

The jumonji domain is a highly conserved bipartite domain made up of two subdomains, jmjN and jmjC, which is found in many eukaryotic transcription factors. The jmjC domain was recently shown to possess the histone demethylase activity. Here we show that the jmjN and jmjC domains of the yeast zinc finger protein Gis1 interact in a two-hybrid system with 19 yeast proteins that include the RecQ helicase Sgs1, the silencing factors Esc1 and Sir4, the URI-type prefoldin Bud27 and the PIAS type SUMO ligase Nfi1/Siz2. Extensive interaction cross dependencies further suggest that the proteins form a larger complex. Consistent with this, 16 of the proteins also interact with a Bud27 two-hybrid bait, and three of them co-precipitate with TAP-tagged Gis1. The Gis1 jumonji domain can repress transcription when recruited to a promoter as a lexA fusion. This effect is dependent on both the jmjN and jmjC subdomains, as were all 19 two-hybrid interactions, indicating that the two subdomains form a single functional unit. The human Sgs1 homolog WRN also interacts with the Gis1 jumonji domain. Finally, we note that several jumonji domain interactors are related to proteins that are found in mammalian PML nuclear bodies.
Mol Genet Genomics 2007 Jan
PMID:The jmjN and jmjC domains of the yeast zinc finger protein Gis1 interact with 19 proteins involved in transcription, sumoylation and DNA repair. 1704 93

Posttranslational modification of chromatin by histone methylation has wide-ranging effects on nuclear function, including transcriptional regulation, maintenance of genome integrity, and epigenetic inheritance. The enzymes utilized to place histone methylation marks are well characterized, but the identity of a histone demethylation system remained elusive until recently. The discovery of histone demethylase enzymes capable of directly removing methyl groups from modified lysine residues has demonstrated that histone methylation is a dynamic modification. The most extensive family of histone demethylase enzymes identified so far contains a JmjC domain and catalyzes demethylation through a hydroxylation reaction. Here, we identify PLU-1, a transcriptional repressor implicated in breast cancer, as a histone demethylase enzyme that has the ability to reverse the trimethyl H3K4 modification state. Furthermore, we reveal that PLU-1-mediated H3K4 demethylase activity plays an important role in the proliferative capacity of breast cancer cells through repression of tumor suppressor genes, including BRCA1.
Mol Cell 2007 Mar 23
PMID:PLU-1 is an H3K4 demethylase involved in transcriptional repression and breast cancer cell proliferation. 1736 12

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.
Mol Cell Biol 2007 Jun
PMID:Demethylation of histone H3K36 and H3K9 by Rph1: a vestige of an H3K9 methylation system in Saccharomyces cerevisiae? 1737 40

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.
Mol Cell Biol 2007 Jun
PMID:Genome-wide dynamics of SAPHIRE, an essential complex for gene activation and chromatin boundaries. 1737 46

Histone methylation plays important roles in the regulation of chromatin dynamics and transcription. Steady-state levels of histone lysine methylation are regulated by a balance between enzymes that catalyze either the addition or removal of methyl groups. Using an activity-based biochemical approach, we recently uncovered the JmjC domain as an evolutionarily conserved signature motif for histone demethylases. Furthermore, we demonstrated that Jhd1, a JmjC domain-containing protein in Saccharomyces cerevisiae, is an H3K36-specific demethylase. Here we report further characterization of Jhd1. Similar to its mammalian homolog, Jhd1-catalyzed histone demethylation requires iron and alpha-ketoglutarate as cofactors. Mutation and deletion studies indicate that the JmjC domain and adjacent sequences are critical for Jhd1 enzymatic activity, while the N-terminal PHD domain is dispensable. Overexpression of JHD1 results in a global reduction of H3K36 methylation in vivo. Finally, chromatin immunoprecipitation-coupled microarray studies reveal subtle changes in the distribution of H3K36me2 upon overexpression or deletion of JHD1. Our studies establish Jhd1 as a histone demethylase in budding yeast and suggest that Jhd1 functions to maintain the fidelity of histone methylation patterns along transcription units.
Mol Cell Biol 2007 Jul
PMID:The Saccharomyces cerevisiae histone demethylase Jhd1 fine-tunes the distribution of H3K36me2. 1747 May 55

JMJD2A is a JmjC histone demethylase (HDM) that catalyzes the demethylation of di- and trimethylated Lys9 and Lys36 in histone H3 (H3K9me2/3 and H3K36me2/3). Here we present the crystal structures of the JMJD2A catalytic domain in complex with H3K9me3, H3K36me2 and H3K36me3 peptides. The structures reveal that histone substrates are recognized through a network of backbone hydrogen bonds and hydrophobic interactions that deposit the trimethyllysine into the active site. The trimethylated epsilon-ammonium cation is coordinated within a methylammonium-binding pocket through carbon-oxygen (CH...O) hydrogen bonds that position one of the zeta-methyl groups adjacent to the Fe(II) center for hydroxylation and demethylation. Mutations of the residues comprising this pocket abrogate demethylation by JMJD2A, with the exception of an S288A substitution, which augments activity, particularly toward H3K9me2. We propose that this residue modulates the methylation-state specificities of JMJD2 enzymes and other trimethyllysine-specific JmjC HDMs.
Nat Struct Mol Biol 2007 Aug
PMID:Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase. 1767 28

Fertilized egg or totipotent zygote undergoes cleavage divisions to form a blastocyst, consisting of outer trophoectoderm cells and inner cell mass with pluripotent primitive ectoderm cells. Epigenetic reprogramming, erasure and maintenance of epigenetic modification, occurs during early embryogenesis. In 2004, we identified and characterized JMJD2A/JHDM3A, JMJD2B, JMJD2C, JMJD2D, JMJD2E and JMJD2F. JMJD2A, JMJD2B and JMJD2C share the common domain architecture with JmjN, JmjC, two PHD, and two TUDOR domains. In 2006, other groups characterized JMJD2 family members as the H3K9 and/or H3K36 histone demethylases. Here, comparative integromics analyses on JMJD2A, JMJD2B and JMJD2C were carried out. Mouse Jmjd2a was expressed in fertilized egg and 2-cell embryos, while human JMJD2A was expressed in undifferentiated and differentiated ES cells. AP1-binding site and six bHLH-binding sites within intron 13 of human JMJD2A gene were conserved in mouse Jmjd2a gene. Mouse Jmjd2b was expressed in 8-cell embryos and undifferentiated ES cells, while human JMJD2B was expressed in undifferentiated and differentiated ES cells. Two GATA-binding sites within intron 6 of human JMJD2B gene were conserved in mouse Jmjd2b gene. Mouse Jmjd2c and human JMJD2C were preferentially expressed in undifferentiated ES cells. Four NANOG-binding sites, one TCF/ LEF-binding site, and one bHLH-binding site were located within evolutionary conserved region at the 3'-flanking region of human JMJD2C gene. NANOG- TCF/LEF-, and bHLH-binding sites within the 3'-flanking region of human JMJD2C gene were conserved in chimpanzee, cow, mouse and rat JMJD2C othologs. Together these facts indicate that JMJD2C is the evolutionarily conserved target of Homeo-domain transcription factor NANOG, and that JMJD2C is the histone demethylase implicated in the epigenetic reprogramming during the early embryogenesis.
Int J Mol Med 2007 Aug
PMID:Comparative integromics on JMJD2A, JMJD2B and JMJD2C: preferential expression of JMJD2C in undifferentiated ES cells. 1761 47


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