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PubMed2000

Jumonji is a nuclear protein that participates in the negative regulation of cell growth.

The jumonji (jmj) gene, obtained by a gene trap strategy, is essential for mouse embryogenesis and is suggested to play important roles in cell growth during development. The amino acid sequence of the Jmj protein includes a nuclear localization signal and a DNA binding motif called the AT-rich interaction domain (ARID). To investigate the biological functions of the Jmj protein, we prepared specific antibodies. Using these antibodies, we showed that the Jmj protein is a 160-kDa protein and localizes in the nuclei of COS-7 cells transfected with jmj cDNA and megakaryocytes from fetal liver which show strong endogenous expression of the jmj gene. Moreover, overexpression of the Jmj protein in COS-7 and NIH3T3 cells remarkably reduced cell proliferation compared with control cells transfected with vector alone. These results show that the Jmj protein acts in cell nuclei and participates in the negative regulation of cell proliferation signaling.

3T3 Cells↗
PubMed1995

Generation of a transcription map at the HSD17B locus centromeric to BRCA1 at 17q21.

A detailed transcription map of the 320-kb region containing the HSD17B locus on chromosome 17 was generated. Thirty unique cDNA fragments, retrieved following the hybridization of immobilized YACs to primary pools of cDNAs prepared from RNA of mammary gland, ovary, placenta, and the Caco-2 cell line, were aligned into 10 transcription units by physical mapping and hybridization to RNAs of a series of tissues. The cDNAs were then further characterized by sequencing and used to screen mammary gland cDNA libraries. Fragments corresponding to the broadly expressed gamma-tubulin and Ki antigen genes were identified. A full-length cDNA clone encoding a 117-amino-acid protein homologous to the rat ribosomal protein L34 was isolated. Portions of genes with restricted patterns of expression were also obtained, including the previously characterized HSD17B1. One new gene, for which a full-length cDNA was isolated, was found to have an interesting tissue-specific pattern of expression with abundant mRNA in both the colon and the testis and in the mammary carcinoma cell line BT-474. This contrasted with the barely detectable level observed in several tissues including normal mammary gland. Of the five additional transcription units identified, one showed no similarity, two showed identity to human expressed sequences, and two displayed similarity to genes of animal species by amino acid alignment. These latter cDNA clones include potential homologues of a rat nuclear tyrosine phosphatase and of a factor of Drosophila that is known to be involved in the negative regulation of transcription of segment identity genes.

Amino Acid Sequence↗
PubMed1996

Characterization of EZH1, a human homolog of Drosophila Enhancer of zeste near BRCA1.

Recent transcription mapping efforts within chromosome 17q21 have led to the identification of a human homolog of the Drosophila gene Enhancer of zeste, E(z). A member of the Polycomb group (Pc-G) of proteins, Drosophila E(z) acts as a negative regulator of the segment identity genes of the Antennapedia and Bithorax complexes. Here we report the full-length protein coding sequence of human EZH1 (Enhancer of zeste homolog 1) and compare the respective protein sequences in both species. EZH1 encodes a protein of 747 amino acids that displays 55% amino acid identity overall (70% similarity) with Drosophila E(z). The strongest homology was noted (79% identity, 89% similarity) within the carboxy-terminal 245 amino acids, including the SET domain, a region of E(z) also conserved in other Drosophila proteins with roles in development and/or chromatin structure. A large Cysrich region with a novel spatial pattern of cysteine residues was also conserved in both EZH1 and E(z). The strong sequence conservation suggest potential roles for EZH1 in human development as a transcriptional regulator and as a component of protein complexes that stably maintain heterochromatin. EZH1 is expressed as two major transcripts in all adult and fetal human tissues surveyed; comparison of cloned cDNAs suggests that alternative splicing may account for at least part of the transcript size difference. Analysis of one cDNA revealed an unusual splicing event involving EZH1 and a tandemly linked gene GPR2 and suggests a potential mechanism for modifying the EZH1 protein in the conserved C-terminal domain. The sequence and isolated cDNAs will provide useful reagents for determining the function of EZH1 and the importance of the evolutionarily conserved domains.

Adult↗
PubMed1996

Cloning of a human homolog of the Drosophila enhancer of zeste gene (EZH2) that maps to chromosome 21q22.2.

To identify genes that map on human chromosome 21 (HC21) and that may contribute to the phenotype of Down syndrome (DS), exon trapping was applied to cosmid DNA from an HC21-specific library LL21NCO2-Q. More than 550 potential exons were cloned and partially characterized. One of these, hmc23b04 (GenBank X88270) showed strong homology to the Drosophila Enhancer of zeste protein (GenBank U00180) from amino acid 665 to 694 (p = 7.6 x 10(-11). We have cloned the full-length cDNA for this human homolog of the Drosophila E(z) gene (termed EZH2) and mapped it to within YACs 64f11 and 809b11 between markers D21S65 and ERG on human chromosome 21q22.2. Sequence analysis indicates that EZH2 encodes a 746-amino-acid polypeptide that shows 60.5% identity to the Drosophila E(z) protein and contains a trithorax-like domain and a DNA-binding motif. Northern blot analysis revealed that EZH2 is expressed in several tissues. Alternatively spliced mRNA species have been observed. The Drosophila E(z) protein is a member of the polycomb group genes that maintain homeotic gene repression and are thought to control gene expression by regulating chromatin. The strong sequence conservation suggests a possible function of EZH2 in regulation of gene transcription and chromatin structure; it may therefore contribute to certain phenotypes of Down syndrome by altered regulation of its target genes.

Alternative Splicing↗
PubMed1998

The murine Polycomb-group gene eed and its human orthologue: functional implications of evolutionary conservation.

Similar to Drosophila, murine Polycomb-group (PcG) genes regulate anterior-posterior patterning of segmented axial structures by transcriptional repression of homeotic gene expression. The murine PcG gene eed (embryonic ectoderm development) encodes a 441-amino-acid protein with five WD motifs which, except for the amino terminus, is highly homologous to Drosophila ESC (Extra Sex Combs). Here, sequence and expression analysis as well as chromosomal mapping of the human orthologue of eed is described. Absolute conservation of the human eed protein along with significant divergence at the nucleotide level reveals functional constraints operating on all residues. The human orthologue appears to be ubiquitously expressed and maps to chromsome 11q14.2-q22.3. Using the first WD motif of the beta-subunit of the bovine G protein as a structural reference, the predicted locations of two previously identified eed point mutations (A. Schumacher et al., 1996, Nature 383: 250-253) are also reported herein. The proline substitution (L196P) in the second WD motif of the l7Rn5(3354SB) null allele maps to the internal core of the inner end of the beta-propeller blade and is likely to disrupt protein folding. In contrast, the asparagine substitution (I193N) in the second WD motif of the hypomorphic l7Rn5(1989SB) allele maps onto the surface of the beta-propeller blade near the central cavity and may affect surface interactions without compromising propeller packing. These results illustrate the critical importance of all residues for eed function in mammals and support a model whereby the amino terminus might implement function(s) related to embryonic development in higher organisms.

5' Untranslated Regions↗
PubMed1995

Genetic interactions and dosage effects of Polycomb group genes of Drosophila.

The Polycomb (Pc) group of genes are required for maintenance of cell determination in Drosophila melanogaster. At least 11 Pc group genes have been described and there may be up to 40; all are required for normal regulation of homeotic genes, but as a group, their phenotypes are rather diverse. It has been suggested that the products of Pc group genes might be members of a heteromeric complex that acts to regulate the chromatin structure of target loci. We examined the phenotypes of adult flies heterozygous for every pairwise combination of Pc group genes in an attempt to subdivide the Pc group functionally. The results support the idea that Additional sex combs (Asx), Pc, Polycomblike (Pcl), Posterior sex combs (Psc), Sex combs on midleg (Scm), and Sex combs extra (Sce) have similar functions in some imaginal tissues. We show genetic interactions among extra sex combs (esc) and Asx, Enhancer of Pc, Pcl, Enhancer of zeste E(z), and super sex combs and reassess the idea that most Pc group genes function independently of esc. Most duplications of Pc group genes neither exhibit anterior transformations nor suppress the extra sex comb phenotype of Pc group mutations, suggesting that not all Pc group genes behave as predicted by the mass-action model. Surprisingly, duplications of E(z) enhance homeotic phenotypes of esc mutants. Flies with increasing doses of esc+ exhibit anterior transformations, but these are not enhanced by mutations in trithorax group genes. The results are discussed with respect to current models of Pc group function.

Alleles↗
PubMed2000

Role of Enhancer of zeste on the production of Drosophila melanogaster pheromonal hydrocarbons.

In a search for genes controlling the production of Drosophila melanogaster contact pheromones, the gene Enhancer of zeste [E(z)] was found to be one player. Flies mutant for either the amorphic or the antimorphic allele of E(z) showed a similar hydrocarbon phenotype as those with the overlapping Df lxd(15) deficiency: decreased amounts of total hydrocarbons and especially unsaturated ones in both sexes. The decrease in the level of D. melanogaster female sex pheromone 7,11-heptacosadiene was dramatic and was correlated with an increase in 7-heptacosene. Females mutant for a gain-of-function allele had increased amounts of total hydrocarbons with wild-type proportions of dienes. Thus the E(z) gene seems to affect hydrocarbon biosynthesis, especially its desaturation steps and even more so the female-specific desaturation step transforming 7-monoenic fatty acids to 7,11-dienic ones and leading to female pheromones.

Animals↗
PubMed2005

Developmental regulation of Suz 12 localization.

Chromatin modifications are among the epigenetic alterations essential for genetic reprogramming during development. The Polycomb group (PcG) gene family mediates chromatin modifications that contribute to developmentally regulated transcriptional silencing. Trimethylation of histone H3 on lysine 27, mediated by a PcG protein complex consisting of Eed, Ezh2, and Suz12, is integral in differentiation, stem cell self-renewal, and tumorigenesis. Eed and Ezh2 are also implicated in the developmentally regulated silencing of the inactive X chromosome, as they are transiently enriched on the inactive X chromosome when X chromosome silencing is initiated. Here we analyze the dynamic localization of Suz12 during cellular differentiation and X-inactivation. Though Suz12 is a requisite member of the Eed/Ezh2 complexes, we found that Suz12 exhibits a notable difference from Ezh2 and Eed: while Ezh2 and Eed levels decrease during stem cell differentiation, Suz12 levels remain constant. Despite the differential regulation in abundance of Suz12 and Eed/Ezh2, Suz12 is also transiently enriched on the Xi during early stages of X-inactivation, and this accumulation is Xist RNA dependent. These results suggest that Suz12 may have a function that is not mediated by its association with Eed and Ezh2, and that this additional function is not involved in the regulation of X-inactivation.

Animals↗
PubMed2003

Polycomb-group proteins are involved in silencing processes caused by a transgenic element from the murine imprinted H19/Igf2 region in Drosophila.

A subset of autosomal genes undergo genomic imprinting which results in expression from only the paternal or maternal chromosome. While this phenomenon is restricted to mammals and angiosperms, the underlying silencing mechanisms appear to be evolutionarily conserved. A biallelically unmethylated DNaseI hypersensitive region (A6-A4) between the imprinted Igf2 and H19 genes is conserved in humans and mice and functions as a tissue-specific maintenance element for the imprinted growth factor IGF2. In order to analyse A6-A4 for potentially conserved transcriptional maintenance properties, we have generated transgenic Drosophila harbouring the element in a reporter construct. These flies depicted silencing of the reporter genes lacZ and mini -white. The silenced state of the mini -white gene showed variegation and sensitivity to temperature changes. In addition, two members of the conserved Polycomb group, Enhancer of zeste and Posterior sex combs, were needed for repression. Polycomb group proteins are essential for gene silencing during development. Our results indicate that Polycomb group proteins may also be involved in the regulation of mammalian imprinted genes.

Animals↗
PubMed2000

Effects of Polycomb group mutations on the expression of Ultrabithorax in the Drosophila visceral mesoderm.

The Polycomb group (PcG) genes encode repressors of many developmental regulatory genes including homeotic genes and are known to act by modifying chromatin structure through complex formation. We describe how Ultrabithorax (Ubx) expression is affected by the PcG mutants in the visceral mesoderm. Mutant embryos of the genes extra sex combs (esc), Polycomb (Pc), additional sex combs (Asx) and pleiohomeotic (pho) were examined. In each mutation, Ubx was ectopically expressed outside of their normal domains along the anterior-posterior axis in the visceral mesoderm, which is consistent with the effect of PcG proteins repressing the homeotic genes in other tissues. All of these four PcG mutations exhibit complete or partial lack of midgut constriction. However, two thirds of esc mutant embryos did not show Ubx expression in parasegment 7 (PS7). Even in the embryos showing ectopic Ubx expression, the level of Ubx expression in the PcG mutations was weaker than that in normal embryos. We suggest that in PcG mutations the ectopic Ubx expression is caused by lack of PcG repressor proteins, while the weaker or lack of Ubx expression is due to the repression of Ubx by Abd-B protein which is ectopically expressed in PcG mutations as well.

Animals↗
PubMed1995

The Drosophila extra sex combs protein contains WD motifs essential for its function as a repressor of homeotic genes.

Extra sex combs is a member of the Polycomb Group genes, whose products are required for stable long term transcriptional repression of the homeotic genes of the Bithorax and Antennapedia complexes. The Pc-G proteins are required to maintain the spatially restricted domains of homeotic gene expression established by the transiently expressed repressors, e.g., hunchback, but are not required for the functioning of these early repressors. This implies two distinct modes of repression and raises the question: how does the transition from early transient repression to stable Pc-G-mediated repression occur? While other Pc-G proteins are required continuously throughout development, the esc RNA is only present transiently in early embryos, suggesting that esc may play a role in mediating this transition to stable long term Pc-G-mediated repression. The predicted esc protein contains multiple copies of the WD motif, found in G-protein beta subunits as well as non-G proteins involved in diverse cellular functions, including transcriptional repression. The sequence alterations of a number of esc mutations cause amino acid substitutions within the WD repeats, identifying them as essential for the function of the esc protein as a repressor of homeotic gene expression. Other WD proteins are components of reversible macromolecular assemblies and the WD motif has recently been directly implicated in mediating interactions with other proteins in such complexes. We propose that the esc protein is similarly involved in the initial recruitment of Pc-G repressors to the homeotic genes to establish their stable long term repression.

Amino Acid Sequence↗
PubMed2004

Modifiers of the jumonji mutation downregulate cyclin D1 expression and cardiac cell proliferation.

Cell proliferation is an important factor in various developmental processes in tissue morphogenesis, and is strictly regulated spatiotemporally. jumonji (jmj) deficient mice with a C3H/He background show hyperproliferation of cardiac myocytes and die probably of the phenotype around embryonic day 11.5. Analyses of the abnormalities revealed that repression of cyclin D1 expression by jmj is necessary for downregulation of cardiac myocyte proliferation. On the other hand, jmj mutant mice with a BALB/c background die around E14.5, suggesting that genetic background modifies hyperproliferation in the heart and timing of lethality. Here, we demonstrated that the hyperproliferation was not observed, and that cell proliferation and expression of cyclin D1 were downregulated properly in the cardiac ventricles of jmj mutant mice with a BALB/c background. These results suggest the modifier(s) of the jmj mutation can downregulate cardiac cell proliferation by repressing cyclin D1 expression in the same way as jmj.

Animals↗
PubMed2004

Cardiac abnormalities cause early lethality of jumonji mutant mice.

jumonji (jmj) mutant mice, obtained by a gene trap strategy, showed several morphological abnormalities including neural tube and cardiac defects, and died in utero around embryonic day 11.5 (E11.5). It is unknown what causes the embryonic lethality. Here, we demonstrate that exogenous expression of jmj gene in the heart of jmj mutant mice rescued the morphological phenotypes in the heart, and these embryos survived until E13.5. These results suggest that there are at least two lethal periods in jmj mutant mice, and that cardiac abnormalities may cause the earlier lethality. In addition, the rescue of the cardiac abnormalities by the jmj transgene provided solid evidence that the cardiac abnormalities resulted from mutation of the jmj gene.

Animals↗
PubMed2005

The N-terminus of Drosophila ESC mediates its phosphorylation and dimerization.

The ESC protein, like other Polycomb Group proteins, is required for heritable silencing of the homeotic genes. ESC is phosphorylated in vivo, but the region of ESC that is phosphorylated and its consequences are not known. Here, we show that the amino-terminal region of ESC (residues 1-60) mediates its phosphorylation and dimerization. Phosphorylation of ESC1-60 in vitro by CK1 and CK2 strongly enhances its dimerization. Both phosphorylation and dimerization are conserved in the mammalian ESC homolog EED, suggesting that they play important roles in vivo. One role is suggested by the effect of phosphatase treatment on native ESC complexes, which does not affect the integrity of the 600 kDa ESC/E(Z) complex, but eliminates the 1 MDa ESC/E(Z) complex, which is distinguished from the former by the presence of the additional subunits PCL and RPD3. Thus, stability and perhaps assembly of larger ESC complexes may depend on ESC phosphorylation.

Amino Acid Sequence↗
PubMed2006

Association of Polycomb group SUZ12 with WD-repeat protein MEP50 that binds to histone H2A selectively in vitro.

SUZ12 is a Polycomb group protein that forms Polycomb repressive complexes (PRC2/3) together with EED and histone methyltransferase EZH2. Although the essential role of SUZ12 in regulating the activity of the PRC2/3 complexes has been demonstrated, additional function of this protein was suggested. Here, we show that SUZ12 interacts with WD-repeat protein MEP50 in vitro and in vivo. We show that the MEP50 binds histone H2A selectively among core histones, and mediates transcriptional repression of protein arginine methyltransferase PRMT5, which is known to methylate H2A and H4. These results suggest that SUZ12 might have a role in transcriptional regulation through physical interaction with MEP50 that can be an adaptor between PRMT5 and its substrate H2A.

Adaptor Proteins, Signal Transducing↗