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PubMed2006

Alternative ESC and ESC-like subunits of a polycomb group histone methyltransferase complex are differentially deployed during Drosophila development.

The Extra sex combs (ESC) protein is a Polycomb group (PcG) repressor that is a key noncatalytic subunit in the ESC-Enhancer of zeste [E(Z)] histone methyltransferase complex. Survival of esc homozygotes to adulthood based solely on maternal product and peak ESC expression during embryonic stages indicate that ESC is most critical during early development. In contrast, two other PcG repressors in the same complex, E(Z) and Suppressor of zeste-12 [SU(Z)12], are required throughout development for viability and Hox gene repression. Here we describe a novel fly PcG repressor, called ESC-Like (ESCL), whose biochemical, molecular, and genetic properties can explain the long-standing paradox of ESC dispensability during postembryonic times. Developmental Western blots show that ESCL, which is 60% identical to ESC, is expressed with peak abundance during postembryonic stages. Recombinant complexes containing ESCL in place of ESC can methylate histone H3 with activity levels, and lysine specificity for K27, similar to that of the ESC-containing complex. Coimmunoprecipitations show that ESCL associates with E(Z) in postembryonic cells and chromatin immunoprecipitations show that ESCL tracks closely with E(Z) on Ubx regulatory DNA in wing discs. Furthermore, reduced escl+ dosage enhances esc loss-of-function phenotypes and double RNA interference knockdown of ESC/ESCL in wing disc-derived cells causes Ubx derepression. These results suggest that ESCL and ESC have similar functions in E(Z) methyltransferase complexes but are differentially deployed as development proceeds.

Amino Acid Sequence↗
PubMed2000

Jumonji, a nuclear protein that is necessary for normal heart development.

Jumonji (jmj) was cloned in a gene trap screen to identify and mutagenize genes important for heart development. To investigate the role of jmj in heart development, we generated mice homozygous for the jmj mutation. The jmj homozygous mouse embryos showed heart malformations, including ventricular septal defect, noncompaction of the ventricular wall, double-outlet right ventricle, and dilated atria. The jmj mutants died soon after birth, apparently as a result of respiratory insufficiency caused by rib and sternum defects in addition to the heart defects. In situ hybridization analyses suggested that cardiomyocytes were differentiated but developmental regulation of chamber-specific genes was defective in fetal hearts. Expression of jmj was detected in the myocardium, especially in the interventricular septum, ventricular wall, and outflow tract, which correlated well with the locations of defects observed in the hearts of mutant mice. Homozygous embryos failed to express the jmj transcript in all tissues except in the nervous system. Confocal microscopic examination using anti-JMJ antibodies indicated that the JMJ protein was localized in the nuclei of cells transfected with jmj. These data demonstrate that JMJ is a nuclear protein, which is essential for normal heart development and function.

Animals↗
PubMed2001

Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma.

Polycomb-group (PcG) proteins, such as BMI-1 and EZH2, form multimeric gene-repressing complexes involved in axial patterning, hematopoiesis, and cell cycle regulation. In addition, BMI-1 is involved in experimental lymphomagenesis. Little is known about its role in human lymphomagenesis. Here, BMI-1 and EZH2 expression patterns are analyzed in a variety of B-cell non-Hodgkin lymphomas (B-NHLs), including small lymphocytic lymphoma, follicular lymphoma, large B-cell lymphoma, mantle-cell lymphoma, and Burkitt lymphoma. In contrast to the mutually exclusive pattern of BMI-1 and EZH2 in reactive follicles, the neoplastic cells in B-NHLs of intermediate- and high-grade malignancy showed strong coexpression of BMI-1 and EZH2. This pattern overlapped with the expression of Mib-1/Ki-67, a marker for proliferation. Neoplastic cells in B-NHL of low-grade malignancy were either BMI-1(low)/EZH2(+) (neoplastic centroblasts) or BMI-1(low)EZH2(-) (neoplastic centrocytes). These observations show that low-, intermediate-, and high grade B-NHLs are associated with increased coexpression of the BMI-1 and EZH2 PcG proteins, whose normal expression pattern is mutually exclusive. This expression pattern is probably caused by a failure to down-regulate BMI-1 in dividing neoplastic cells, because BMI-1 expression is absent from normal dividing B cells. These observations are in agreement with findings in studies of Bmi-1 transgenic mice. The extent of BMI-1/EZH2 coexpression correlated with clinical grade and the presence of Mib-1/Ki-67 expression, suggesting that the irregular expression of BMI-1 and EZH2 is an early event in the formation of B-NHL. This points to a role for abnormal PcG expression in human lymphomagenesis. (Blood. 2001;97:3896-3901)

Adolescent↗
PubMed2006

Corto and DSP1 interact and bind to a maintenance element of the Scr Hox gene: understanding the role of Enhancers of trithorax and Polycomb.

BACKGROUND: Polycomb-group genes (PcG) encode proteins that maintain homeotic (Hox) gene repression throughout development. Conversely, trithorax-group (trxG) genes encode positive factors required for maintenance of long term Hox gene activation. Both kinds of factors bind chromatin regions called maintenance elements (ME). Our previous work has shown that corto, which codes for a chromodomain protein, and dsp1, which codes for an HMGB protein, belong to a class of genes called the Enhancers of trithorax and Polycomb (ETP) that interact with both PcG and trxG. Moreover, dsp1 interacts with the Hox gene Scr, the DSP1 protein is present on a Scr ME in S2 cells but not in embryos. To understand better the role of ETP, we addressed genetic and molecular interactions between corto and dsp1. RESULTS: We show that Corto and DSP1 proteins co-localize at 91 sites on polytene chromosomes and co-immunoprecipitate in embryos. They interact directly through the DSP1 HMG-boxes and the amino-part of Corto, which contains a chromodomain. In order to search for a common target, we performed a genetic interaction analysis. We observed that corto mutants suppressed dsp11 sex comb phenotypes and enhanced AntpScx phenotypes, suggesting that corto and dsp1 are simultaneously involved in the regulation of Scr. Using chromatin immunoprecipitation of the Scr ME, we found that Corto was present on this ME both in Drosophila S2 cells and in embryos, whereas DSP1 was present only in S2 cells. CONCLUSION: Our results reveal that the proteins Corto and DSP1 are differently recruited to a Scr ME depending on whether the ME is active, as seen in S2 cells, or inactive, as in most embryonic cells. The presence of a given combination of ETPs on an ME would control the recruitment of either PcG or TrxG complexes, propagating the silenced or active state.

Animals↗
PubMed1992

Ten different Polycomb group genes are required for spatial control of the abdA and AbdB homeotic products.

Mutations in genes of the Polycomb (Pc) group cause abnormal segmental development due to ectopic expression of the homeotic products of the Antennapedia and bithorax complexes. Here the requirements for Pc group genes in controlling the abdA and AbdB products of the bithorax complex are described. Embryos containing mutations in the genes Polycomb (Pc), extra sex combs (esc), Enhancer of zeste [E(z)], polyhomeotic (ph), Sex comb on midleg (Scm), Polycomb-like (Pcl), Sex comb extra (Sce), Additional sex combs (Asx), Posterior sex combs (Psc) and pleiohomeotic (pho) were examined. In every case, both abdA and AbdB are expressed outside of their normal domains along the anterior-posterior (A-P) axis, consistent with these Pc group products acting in a single pathway or molecular complex. The earliest detectable ectopic expression is highest in the parasegments immediately adjacent to the normal expression boundary. Surprisingly, in the most severe Pc group mutants, the earliest ectopic AbdB is distributed in a pair-rule pattern. At all stages, ectopic abdA in the epidermis is highest along the anterior edges of the parasegments, in a pattern that mimics the normal abdA cell-specific pattern. These examples of highly patterned mis-expression show that Pc group mutations do not cause indiscriminate activation of homeotic products. We suggest that the ectopic expression patterns result from factors that normally activate abdA and AbdB only in certain parasegments, but that in Pc group mutants these factors gain access to regulatory DNA in all parasegments.

Animals↗
PubMed1996

The Drosophila Enhancer of zeste gene encodes a chromosomal protein: examination of wild-type and mutant protein distribution.

The Drosophila Enhancer of zeste [E(z)] gene is a member of the Polycomb-group and, as such, is involved in maintaining the transcriptional repression of the homeotic genes of the Antennapedia (ANT-C) and bithorax (BX-C) complexes. It has been proposed that Polycomb-group (Pc-G)-mediated silencing requires the formation of heteromeric protein complexes which modify the chromatin structure of target genes. We describe the in vivo distribution of the E(Z) protein and show it to be ubiquitously present in embryonic and larval nuclei. In salivary gland polytenized nuclei, the identifiable E(Z) chromosome binding sites are a subset of those described for other Polycomb-group proteins, suggesting that E(Z) may also participate in Polycomb-group complexes. E(Z) binds to chromosomes in a DNA sequence-dependent manner, as illustrated by the creation of a new E(Z)-binding site at the location of a P element reporter construct that previously has been shown to contain a Polycomb response element (PRE). We also present the sequences of one null and three temperature-sensitive E(z) alleles, describe the effects these mutations have on the in vivo distribution of E(Z) protein and discuss their implications concerning putative functional domains. Finally, we describe the effect a trithorax mutation has on E(Z) chromosome binding.

Animals↗
PubMed1998

The Drosophila Polycomb Group proteins ESC and E(Z) bind directly to each other and co-localize at multiple chromosomal sites.

The Polycomb Group gene esc encodes an evolutionarily conserved protein required for transcriptional silencing of the homeotic genes. Unlike other Polycomb Group genes, esc is expressed and apparently required only during early embryogenesis, suggesting it is required for the initial establishment of silencing but not for its subsequent maintenance. We present evidence that the ESC protein interacts directly with E(Z), another Polycomb Group protein required for silencing of the homeotic genes. We show that the most highly conserved region of ESC, containing seven WD motifs that are predicted to fold into a beta-propeller structure, mediate its binding to a conserved N-terminal region of E(Z). Mutations in the WD region that perturb ESC silencing function in vivo also perturb binding to E(Z) in vitro. The entire WD region forms a trypsin-resistant structure, like known beta -propeller domains, and mutations that would affect the predicted ESC beta-propeller perturb its trypsin-resistance, while a putative structure-conserving mutation does not. We show by co-immunoprecipitation that ESC and E(Z) are directly associated in vivo and that they also co-localize at many chromosomal binding sites. Since E(Z) is required for binding of other Polycomb Group proteins to chromosomes, these results suggest that formation of an E(Z):ESC complex at Polycomb Response Elements may be an essential prerequisite for the establishment of silencing.

Amino Acid Sequence↗
PubMed1998

The Polycomb-group gene eed is required for normal morphogenetic movements during gastrulation in the mouse embryo.

We have characterized an induced mutation, called embryonic ectoderm development or eed, that disrupts A-P patterning of the mouse embryo during gastrulation. Positional cloning of this gene revealed it to be the highly conserved homologue of the Drosophila gene extra sex combs, which is required for maintenance of long-term transcriptional repression of homeotic gene expression. Mouse embryos homozygous for loss-of-function alleles of eed initiate gastrulation but display abnormal mesoderm production. Very little embryonic mesoderm is produced; in contrast, extraembryonic mesoderm is relatively abundant. These observations, along with mRNA in situ hybridization analyses, suggested a defect in the anterior primitive streak, from which much of the embryonic mesoderm of the wild-type embryo is derived. To analyse this defect, we initiated clonal analysis of the pre-streak epiblast in eed mutant embryos, using the lineage tracer horseradish peroxidase (HRP). The results of these studies indicate that epiblast cells ingress through the anterior streak, but the newly formed mesoderm does not migrate anteriorly and is mislocalized to the extraembryonic compartment. Abnormal localization of mesoderm to the extraembryonic region did not appear to be due to a restriction and alteration of distal epiblast cell fate, since the majority of clones produced from regions fated to ingress through the anterior streak were mixed, displaying descendants in both embryonic and extraembryonic derivatives. eed mutant embryos also fail to display proper epiblast expansion, particularly with respect to the A-P axis. Based on patterns of clonal spread and calculated clone doubling times for the epiblast, this does not appear to be due to decreased epiblast growth. Rather, epiblast, which is normally fated to make a substantial contribution to the axial midline, appears to make mesoderm preferentially. The data are discussed in terms of global morphogenetic movements in the mouse gastrula and a disruption of signalling activity in the anterior primitive streak.

Animals↗
PubMed2001

Su(z)12, a novel Drosophila Polycomb group gene that is conserved in vertebrates and plants.

In both Drosophila and vertebrates, spatially restricted expression of HOX genes is controlled by the Polycomb group (PcG) repressors. Here we characterize a novel Drosophila PcG gene, Suppressor of zeste 12 (Su(z)12). Su(z)12 mutants exhibit very strong homeotic transformations and Su(z)12 function is required throughout development to maintain the repressed state of HOX genes. Unlike most other PcG mutations, Su(z)12 mutations are strong suppressors of position-effect variegation (PEV), suggesting that Su(z)12 also functions in heterochromatin-mediated repression. Furthermore, Su(z)12 function is required for germ cell development. The Su(z)12 protein is highly conserved in vertebrates and is related to the Arabidopsis proteins EMF2, FIS2 and VRN2. Notably, EMF2 is a repressor of floral homeotic genes. These results suggest that at least some of the regulatory machinery that controls homeotic gene expression is conserved between animals and plants.

Amino Acid Sequence↗
PubMed2001

The Drosophila Polycomb Group proteins ESC and E(Z) are present in a complex containing the histone-binding protein p55 and the histone deacetylase RPD3.

The Drosophila Polycomb Group (PcG) proteins are required for stable long term transcriptional silencing of the homeotic genes. Among PcG genes, esc is unique in being critically required for establishment of PcG-mediated silencing during early embryogenesis, but not for its subsequent maintenance throughout development. We previously showed that ESC is physically associated in vivo with the PcG protein E(Z). We report here that ESC, together with E(Z), is present in a 600 kDa complex that is distinct from complexes containing other PcG proteins. We have purified this ESC complex and show that it also contains the histone deacetylase RPD3 and the histone-binding protein p55, which is also a component of the chromatin remodeling complex NURF and the chromatin assembly complex CAF-1. The association of ESC and E(Z) with p55 and RPD3 is conserved in mammals. We show that RPD3 is required for silencing mediated by a Polycomb response element (PRE) in vivo and that E(Z) and RPD3 are bound to the Ubx PRE in vivo, suggesting that they act directly at the PRE. We propose that histone deacetylation by this complex is a prerequisite for establishment of stable long-term silencing by other continuously required PcG complexes.

Amino Acid Sequence↗
PubMed2004

Nucleotide variation of seven genes in Drosophila kikkawai.

We examined levels and patterns of nucleotide variation in 21 strains of Drosophila kikkawai from Miyako island, Japan for the partial regions of the following seven nuclear genes: Adh, Ddc, esc, ksr, Pgi, su(f), and Tpi. The nucleotide variation at total sites (pi(t)) ranged from 0.0013 in the ksr, to 0.0173 in the Adh. The nucleotide divergence at total sites (K(t)) between D. kikkawai and D. lini ranged from 0.0286 in the Tpi to 0.0687 in the su(f). The levels of nucleotide polymorphism and divergence were heterogeneous among the investigated gene regions. The HKA test, which tests imbalance between the intra and interspecific nucleotide variation, showed that the intraspecific nucleotide variation in the Pgi region was much lower than the interspecific variation, while intraspecific variation in the Tpi region was only slightly lower than interspecific variation. The MK test showed an excess of low frequency replacement polymorphic changes in the Adh region, suggesting that most replacement mutations are deleterious. Fay and Wu's test detected an excess of newly arisen variants in the Ddc region. In total, four of the seven gene regions showed significant deviation from the neutrality.

Alcohol Dehydrogenase↗
PubMed2006

Mutations in the extra sex combs and Enhancer of Polycomb genes increase homologous recombination in somatic cells of Drosophila melanogaster.

We found that heterozygous mutant alleles of E(Pc) and esc increased homologous recombination from an allelic template in somatic cells in a P-element-induced double-strand break repair assay. Flies heterozygous for mutant alleles of these genes showed increased genome stability and decreased levels of apoptosis in imaginal discs and a concomitant increase in survival following ionizing radiation. We propose that this was caused by a genomewide increase in homologous recombination in somatic cells. A double mutant of E(Pc) and esc had no additive effect, showing that these genes act in the same pathway. Finally, we found that a heterozygous deficiency for the histone deacetylase, Rpd3, masked the radiation-resistant phenotype of both esc and E(Pc) mutants. These findings provide evidence for a gene dosage-dependent interaction between the esc/E(z) complex and the Tip60 histone acetyltransferase complex. We propose that esc and E(Pc) mutants enhance homologous recombination by modulating the histone acetylation status of histone H4 at the double-strand break.

Acetylation↗
PubMed2026

Biallelic EZH1 Nonsense Novel Variant in Two Siblings with Neurodevelopmental Disorder and Central Precocious Puberty: A Case Report from a Consanguineous Saudi Family.

Neurodevelopmental disorders (NDDs) are a group of conditions that impair the development and function of the central nervous system. Recently, variants in the EZH1 gene have been associated with neurodevelopmental disorders. Here, using whole-exome sequencing coupled with confirmatory Sanger sequencing, we identified a homozygous nonsense variant in EZH1 in two affected siblings. Both parents were heterozygous carriers of the variant. The variant is predicted to result in a 44-amino acid C-terminal truncation within the catalytic SET domain, leading to loss of protein function. RT-qPCR analysis revealed significantly reduced EZH1 mRNA expression in patient-derived peripheral blood cells. The index patient (female) also exhibited elevated gamma-glutamyl transferase (GGT) levels and hypoalbuminemia, whereas the affected male presented with central precocious puberty. This study further expands the clinical, genetic, and molecular spectrum of EZH1-associated neurodevelopmental disorders by demonstrating that reduced EZH1 expression is consistent with a loss-of-function disease mechanism.

Child↗
PubMed2001

Mapping of the interaction sites between apoptosis linked gene ALG-2 and HEED.

The apoptosis linked gene (ALG-2) is a 22 kDa Ca2+-binding protein of the penta EF-hand motif family. ALG-2 was discovered in a "death trap" assay using T-cell receptor-mediated apoptosis. Depletion of ALG-2 using an anti-sense ALG-2 construct inhibits apoptosis that is induced by several stimuli, such as staurosporin, dexamethason, Fas, and glucocorticoid. The Ca2+-dependent function of ALG-2 is consistent with the observation that the cytoplasmic Ca2+ level is elevated in apoptotic cells. We found that ALG-2 interacted specifically with the carboxy-terminal region of HEED using a yeast two-hybrid assay system. The mutants of HEED were constructed by deleting five WD repeat motifs one by one from the C-terminus of the protein. These mutants of ALG-2 were made by combining the EF hand Ca2+ binding motifs in various ways. Mapping of the interaction sites, using each of the mutants, revealed that the interaction between HEED and a third EF-hand motif of ALG-2 was stronger than the other combination.

Apoptosis Regulatory Proteins↗
PubMed1998

Stage-specific expression of polycomb group genes in human bone marrow cells.

Mammalian Polycomb group (Pc-G) genes, constituting some 5 subfamilies based on their identity to the Drosophila genes Pc, Psc, ph, esc, and E(z), appear to play critical roles in maintaining the transcriptional repression state of Hox/HOM-C genes during development. Despite increasing evidence of the important role of Hox genes in both normal hematopoiesis and leukemic transformation, little is known about the expression and possible function played by Pc-G genes in hematopoietic cells. To address this, we first examined the expression of Pc genes in purified CD34(+) human bone marrow cells by reverse transcriptase-polymerase chain reaction (RT-PCR), using degenerate primers that specifically amplify the majority of Pc genes. This analysis showed the expression of 8 different Pc genes in CD34(+) bone marrow cells, including HP1(Hsalpha), HP1(Hsgamma), the heterochromatin p25 protein, the human homologue of the murine M32 gene, and 4 novel members of this family. To assess whether Pc-G mRNA levels change during differentiation of bone marrow cells, a quantitative RT-PCR method was used to amplify the total cDNA originating from three purified subpopulations of CD34(+) bone marrow cells known to differ in their ability to grow in long-term or semisolid cultures. In sharp contrast to Hox gene expression, which is highest in the most primitive bone marrow cells, these studies show that the expression level of 8 of the 9 Pc-G genes studied (ie, HP1(Hsalpha), HP1(Hsgamma), M31, M32, M33, Mel-18, Mph1/Rae-28, and ENX-1) markedly increases with differentiation of bone marrow cells. Interestingly, BMI-1 exhibits a strikingly different pattern of expression, with high expression levels in primitive cells and very little expression in mature CD34(-) cells. Together, these results document for the first time that differentiation of human bone marrow cells is accompanied by profound changes in Pc-G gene expression levels.

Amino Acid Sequence↗
PubMed1999

Definitive but not primitive hematopoiesis is impaired in jumonji mutant mice.

A novel gene, jumonji was identified by a mouse gene trap strategy. The jumonji gene encodes a protein containing a putative DNA binding domain. The mice homozygous for jumonji gene with a BALB/cA genetic background show hypoplasia of the fetal liver and embryonic lethality, suggesting impaired hematopoiesis. In the peripheral blood of jumonji mutant embryos, the number of fetal liver-derived definitive erythrocytes, but not yolk sac-derived primitive erythrocytes, showed a marked reduction, suggesting that jumonji mutants die of anemia. The defects of definitive erythrocytes in jumonji mutants seemed to be caused by a decrease in the numbers of multiple hematopoietic progenitors including colony-forming unit-spleen (CFU-S) in the fetal liver. However, hematopoietic stem cells (HSCs) in the fetal liver of jumonji mutants could reconstitute the hematopoietic system of lethally irradiated recipients. In the fetal liver, the jumonji gene is expressed in fibroblastic cells and endothelial cells, but not in Lin-/c-Kit+/Sca-1(+) cells known to include HSCs. These results suggest that an environmental defect induce the impaired hematopoiesis in the fetal liver of jumonji mutant embryos.

Animals↗