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PubMed1995

The extra sex combs product contains WD40 repeats and its time of action implies a role distinct from other Polycomb group products.

The extra sex combs (esc) gene product is a transcriptional repressor of homeotic genes. Although it is classified in the Polycomb group (PcG) on the basis of phenotypic criteria, it is distinct from most other PcG repressors in its time of action during development. We describe the temporal profile of esc mRNA expression during embryogenesis and the stage-specific rescue of esc mutants with a heat shock-inducible esc cDNA transformation construct. Both experiments support the idea that esc product plays an early, transient role in repression of homeotic genes. We also present the sequence of a full-length esc cDNA. The predicted esc protein is composed primarily of multiple copies of a repeat motif, termed the WD40 repeat, which are likely used in protein-protein contact. We provide evidence that individual copies of the esc WD40 repeats are needed for function in vivo. We suggest that esc protein is an adaptor that binds to multiple protein partners and assists in the assembly or targeting of other PcG proteins.

Amino Acid Sequence↗

PubMed2004

Expression of the polycomb group gene bmi-1 in the early chick embryo.

Bmi-1 is a protooncogene of the polycomb group that has important functions in self-renewal of adult stem cells and maintenance of anterior identity along the embryonic body axis. Despite these important functions, surprisingly little is known about its distribution pattern in the embryo. Here, we have isolated the chick homologue of bmi-1 and examined its expression pattern from gastrulation through neurulation and establishment of organ rudiments. During gastrulation, bmi-1 transcripts were expressed in the epiblast cells adjacent to the primitive streak. During early nervous system development, robust expression was observed in the open neural plate and later in the dorsal neural tube and much of the brain. Bmi-1 expression was also present in the developing heart primordia and the sensory placodes. The data show that bmi-1 is present in, but not restricted to, tissue containing multipotent precursor cells.

Amino Acid Sequence↗

PubMed2004

The C. elegans Polycomb gene SOP-2 encodes an RNA binding protein.

Epigenetic silencing of Hox cluster genes by Polycomb group (PcG) proteins is thought to involve the formation of a stably inherited repressive chromatin structure. Here we show that the C. elegans-specific PcG protein SOP-2 directly binds to RNA through three nonoverlapping regions, each of which is essential for its localization to characteristic nuclear bodies and for its in vivo function in the repression of Hox genes. Functional studies indicate that the RNA involved in SOP-2 binding is distinct from either siRNA or microRNA. Remarkably, the vertebrate PcG protein Rae28, which is functionally and structurally related to SOP-2, also binds to RNA through an FCS finger domain. Substitution of the Rae28 FCS finger for the essential RNA binding region of SOP-2 partially restores localization to nuclear bodies. These observations suggest that direct binding to RNA is an evolutionarily conserved and potentially important property of PcG proteins.

Animals↗

PubMed2003

Yin Yang 1, a vertebrate polycomb group gene, regulates antero-posterior neural patterning.

Polycomb group (PcG) genes are required for the stable repression of the homeotic genes and other developmentally regulated genes. Yin Yang 1 (YY1), a vertebrate homolog of the Drosophila PcG pleiohomeotic (Pho), is a multifunctional protein that can act as a repressor or activator of transcription. Xenopus YY1 (XYY1) protein was localized in the central nervous system (CNS), particularly anterior neural tube of tailbud stage embryos. To elucidate the role of endogenous XYY1, loss-of-function studies were performed using XYY1 antisense morpholino oligonucleotide (XYY1 MO). Inhibition of XYY1 function resulted in embryos with antero-posterior axial patterning defects and reduction of head structures. XYY1 MO also reduced the expression of En2, a midbrain/hindbrain junction marker, which was rescued by co-injection of XYY1 mRNA. However, XYY1 MO-injection did not affect the expression of HoxB9, a spinal cord marker. These results suggest that YY1 controls antero-posterior patterning of the CNS during Xenopus embryonic development.

Animals↗

PubMed2000

Interaction of the Arabidopsis polycomb group proteins FIE and MEA mediates their common phenotypes.

Genes of the FERTILISATION INDEPENDENT SEED (FIS) class regulate cell proliferation during reproductive development in Arabidopsis [1-5]. The FIS genes FERTILISATION INDEPENDENT ENDOSPERM (FIE) and MEDEA (MEA) encode homologs of animal Polycomb group (Pc-G) proteins, transcriptional regulators that modify chromatin structure and are thought to form multimeric complexes [3-11]. To test whether similarities in fis mutant phenotypes reflect interactions between their protein products, we characterised FIE RNA and protein localisation in vivo, and FIE protein interactions in yeast and in vitro. Expression of FIE mRNA overlaps with that of MEA during embryo sac and seed development and is unaffected in mea mutants. Results from the yeast two-hybrid system and an in vitro pull-down assay indicate that MEA and FIE proteins interact. The relevance of this interaction in vivo is supported by the finding that FIE and MEA co-localise in the nucleus in transfected plant cells. Interaction of MEA and FIE is mediated by the amino-terminal region of MEA. Despite sequence divergence in this domain, MEA can interact with its corresponding animal partner Extrasexcombs (ESC) in the yeast two-hybrid system. We conclude that FIE and MEA act together as part of a multimeric complex and that this accounts for the similarities in mutant phenotypes. We propose that an ancient mechanism for chromatin modification has been independently recruited to different developmental processes in the two kingdoms.

Arabidopsis↗

PubMed2003

Polycomb group regulation of Hox gene expression in C. elegans.

Polycomb group (PcG) chromatin proteins regulate homeotic genes in both animals and plants. In Drosophila and vertebrates, PcG proteins form complexes and maintain early patterns of Hox gene repression, ensuring fidelity of developmental patterning. PcG proteins in C. elegans form a complex and mediate transcriptional silencing in the germline, but no role for the C. elegans PcG homologs in somatic Hox gene regulation has been demonstrated. Surprisingly, we find that the PcG homologs MES-2 [E(Z)] and MES-6 (ESC), along with MES-3, a protein without known homologs, do repress Hox expression in C. elegans. mes mutations cause anteroposterior transformations and disrupt Hox-dependent neuroblast migration. Thus, as in Drosophila, vertebrates, and plants, C. elegans PcG proteins regulate key developmental patterning genes to establish positional identity.

Alleles↗

PubMed2003

Imprinting of the MEA Polycomb gene is controlled by antagonism between MET1 methyltransferase and DME glycosylase.

The MEA Polycomb gene is imprinted in the Arabidopsis endosperm. DME DNA glycosylase activates maternal MEA allele expression in the central cell of the female gametophyte, the progenitor of the endosperm. Maternal mutant dme or mea alleles result in seed abortion. We identified mutations that suppress dme seed abortion and found that they reside in the MET1 methyltransferase gene, which maintains cytosine methylation. Seeds with maternal dme and met1 alleles survive, indicating that suppression occurs in the female gametophyte. Suppression requires a maternal wild-type MEA allele, suggesting that MET1 functions upstream of, or at, MEA. DME activates whereas MET1 suppresses maternal MEA::GFP allele expression in the central cell. MET1 is required for DNA methylation of three regions in the MEA promoter in seeds. Our data suggest that imprinting is controlled in the female gametophyte by antagonism between the two DNA-modifying enzymes, MET1 methyltransferase and DME DNA glycosylase.

Alleles↗

PubMed2004

SUMO modification is required for in vivo Hox gene regulation by the Caenorhabditis elegans Polycomb group protein SOP-2.

Post-translational modification of proteins by the ubiquitin-like molecule SUMO (sumoylation) regulates their subcellular localization and affects their functional properties in vitro, but the physiological function of sumoylation in multicellular organisms is largely unknown. Here, we show that the C. elegans Polycomb group (PcG) protein SOP-2 interacts with the SUMO-conjugating enzyme UBC-9 through its evolutionarily conserved SAM domain. Sumoylation of SOP-2 is required for its localization to nuclear bodies in vivo and for its physiological repression of Hox genes. Global disruption of sumoylation phenocopies a sop-2 mutation by causing ectopic Hox gene expression and homeotic transformations. Chimeric constructs in which the SOP-2 SAM domain is replaced with that derived from fruit fly or mammalian PcG proteins, but not those in which the SOP-2 SAM domain is replaced with the SAM domains of non-PcG proteins, confer appropriate in vivo nuclear localization and Hox gene repression. These observations indicate that sumoylation of PcG proteins, modulated by their evolutionarily conserved SAM domain, is essential to their physiological repression of Hox genes.

Animals↗

PubMed2006

Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer.

Many genes associated with CpG islands undergo de novo methylation in cancer. Studies have suggested that the pattern of this modification may be partially determined by an instructive mechanism that recognizes specifically marked regions of the genome. Using chromatin immunoprecipitation analysis, here we show that genes methylated in cancer cells are specifically packaged with nucleosomes containing histone H3 trimethylated on Lys27. This chromatin mark is established on these unmethylated CpG island genes early in development and then maintained in differentiated cell types by the presence of an EZH2-containing Polycomb complex. In cancer cells, as opposed to normal cells, the presence of this complex brings about the recruitment of DNA methyl transferases, leading to de novo methylation. These results suggest that tumor-specific targeting of de novo methylation is pre-programmed by an established epigenetic system that normally has a role in marking embryonic genes for repression.

Caco-2 Cells↗

PubMed2003

The human L(3)MBT polycomb group protein is a transcriptional repressor and interacts physically and functionally with TEL (ETV6).

H-L(3)MBT, the human homolog of the Drosophila lethal(3)malignant brain tumor protein, is a member of the polycomb group (PcG) of proteins, which function as transcriptional regulators in large protein complexes. Homozygous mutations in the l(3)mbt gene cause brain tumors in Drosophila, identifying l(3)mbt as a tumor suppressor gene. The h-l(3)mbt gene maps to chromosome 20q12, within a common deleted region associated with myeloid hematopoietic malignancies. H-L(3)MBT contains three repeats of 100 residues called MBT repeats, whose function is unknown, and a C-terminal alpha-helical structure, the SPM (SCM, PH, MBT domain, which is structurally similar to the SAM (sterile alpha motif) protein-protein interaction domain, found in several ETS transcription factors, including TEL (translocation Ets leukemia). We report that H-L(3)MBT is a transcriptional repressor and that its activity is largely dependent on the presence of a region containing the three MBT repeats. H-L(3)MBT acts as a histone deacetylase-independent transcriptional repressor, based on its lack of sensitivity to trichostatin A. We found that H-L(3)MBT binds in vivo to TEL, and we have mapped the region of interaction to their respective SPM/SAM domains. We show that the ability of TEL to repress TEL-responsive promoters is enhanced by the presence of H-L(3)MBT, an effect dependent on the H-L(3)MBT and the TEL interacting domains. These experiments suggest that histone deacetylase-independent transcriptional repression by TEL depends on the recruitment of PcG proteins. We speculate that the interaction of TEL with H-L(3)MBT can direct a PcG complex to genes repressed by TEL, stabilizing their repressed state.

Chromosomal Proteins, Non-Histone↗

PubMed2003

Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains.

On the histone H3 tail, Lys 9 and Lys 27 are both methylation sites associated with epigenetic repression, and reside within a highly related sequence motif ARKS. Here we show that the chromodomain proteins Polycomb (Pc) and HP1 (heterochromatin protein 1) are highly discriminatory for binding to these sites in vivo and in vitro. In Drosophila S2 cells, and on polytene chromosomes, methyl-Lys 27 and Pc are both excluded from areas that are enriched in methyl-Lys 9 and HP1. Swapping of the chromodomain regions of Pc and HP1 is sufficient for switching the nuclear localization patterns of these factors, indicating a role for their chromodomains in both target site binding and discrimination. To better understand the molecular basis for the selection of methyl-lysine binding sites, we solved the 1.8 A structure of the Pc chromodomain in complex with a H3 peptide bearing trimethyl-Lys 27, and compared it with our previously determined structure of the HP1 chromodomain in complex with a H3 peptide bearing trimethyl-Lys 9. The Pc chromodomain distinguishes its methylation target on the H3 tail via an extended recognition groove that binds five additional residues preceding the ARKS motif.

Amino Acid Motifs↗

PubMed2003

The Polycomb-group protein MEDEA regulates seed development by controlling expression of the MADS-box gene PHERES1.

The Polycomb-group (PcG) proteins MEDEA, FERTILIZATION INDEPENDENT ENDOSPERM, and FERTILIZATION INDEPENDENT SEED2 regulate seed development in Arabidopsis by controlling embryo and endosperm proliferation. All three of these FIS-class proteins are likely subunits of a multiprotein PcG complex, which epigenetically regulates downstream target genes that were previously unknown. Here we show that the MADS-box gene PHERES1 (PHE1) is commonly deregulated in the fis-class mutants. PHE1 belongs to the evolutionarily ancient type I class of MADS-box proteins that have not yet been assigned any function in plants. Both MEDEA and FIE directly associate with the promoter region of PHE1, suggesting that PHE1 expression is epigenetically regulated by PcG proteins. PHE1 is expressed transiently after fertilization in both the embryo and the endosperm; however, it remains up-regulated in the fis mutants, consistent with the proposed function of the FIS genes as transcriptional repressors. Reduced expression levels of PHE1 in medea mutant seeds can suppress medea seed abortion, indicating a key role of PHE1 repression in seed development. PHE1 expression in a hypomethylated medea mutant background resembles the wild-type expression pattern and is associated with rescue of the medea seed-abortion phenotype. In summary, our results demonstrate that seed abortion in the medea mutant is largely mediated by deregulated expression of the type I MADS-box gene PHE1.

Arabidopsis↗

PubMed2006

Dynamic regulatory interactions of Polycomb group genes: MEDEA autoregulation is required for imprinted gene expression in Arabidopsis.

The imprinted Arabidopsis Polycomb group (PcG) gene MEDEA (MEA), which is homologous to Enhancer of Zeste [E(Z)], is maternally required for normal seed development. Here we show that, unlike known mammalian imprinted genes, MEA regulates its own imprinted expression: It down-regulates the maternal allele around fertilization and maintains the paternal allele silent later during seed development. Autorepression of the maternal MEA allele is direct and independent of the MEA-FIE (FERTILIZATION-INDEPENDENT ENDOSPERM) PcG complex, which is similar to the E(Z)-ESC (Extra sex combs) complex of animals, suggesting a novel mechanism. A complex network of cross-regulatory interactions among the other known members of the MEA-FIE PcG complex implies distinct functions that are dynamically regulated during reproduction.

Alleles↗

PubMed2004

Genetic interaction of an origin recognition complex subunit and the Polycomb group gene MEDEA during seed development.

The eukaryotic origin recognition complex (ORC) is made up of six subunits and functions in nuclear DNA replication, chromatin structure, and gene silencing in both fungi and metazoans. We demonstrate that disruption of a plant ORC subunit homolog, AtORC2 of Arabidopsis (Arabidopsis thaliana), causes a zygotic lethal mutant phenotype (orc2). Seeds of orc2 abort early, typically producing embryos with up to eight cells. Nuclear division in the endosperm is arrested at an earlier developmental stage: only approximately four nuclei are detected in orc2 endosperm. The endosperm nuclei in orc2 are dramatically enlarged, a phenotype that is most similar to class B titan mutants, which include mutants in structural maintenance of chromosomes (SMC) cohesins. The highest levels of ORC2 gene expression were found in preglobular embryos, coinciding with the stage at which homozygous orc2 mutant seeds arrest. The homologs of the other five Arabidopsis ORC subunits are also expressed at this developmental stage. The orc2 mutant phenotype is partly suppressed by a mutation in the Polycomb group gene MEDEA. In double mutants between orc2 and medea (mea), orc2 homozygotes arrest later with a phenotype intermediate between those of mea and orc2 single mutants. Either alterations in chromatin structure or the release of cell cycle checkpoints by the mea mutation may allow more cell and nuclear divisions to occur in orc2 homozygous seeds.

Arabidopsis↗

PubMed1999

Imprinting of the MEDEA polycomb gene in the Arabidopsis endosperm.

In flowering plants, two cells are fertilized in the haploid female gametophyte. Egg and sperm nuclei fuse to form the embryo. A second sperm nucleus fuses with the central cell nucleus that replicates to generate the endosperm, which is a tissue that supports embryo development. MEDEA (MEA) encodes an Arabidopsis SET domain Polycomb protein. Inheritance of a maternal loss-of-function mea allele results in embryo abortion and prolonged endosperm production, irrespective of the genotype of the paternal allele. Thus, only the maternal wild-type MEA allele is required for proper embryo and endosperm development. To understand the molecular mechanism responsible for the parent-of-origin effects of mea mutations on seed development, we compared the expression of maternal and paternal MEA alleles in the progeny of crosses between two Arabidopsis ecotypes. Only the maternal MEA mRNA was detected in the endosperm from seeds at the torpedo stage and later. By contrast, expression of both maternal and paternal MEA alleles was observed in the embryo from seeds at the torpedo stage and later, in seedling, leaf, stem, and root. Thus, MEA is an imprinted gene that displays parent-of-origin-dependent monoallelic expression specifically in the endosperm. These results suggest that the embryo abortion observed in mutant mea seeds is due, at least in part, to a defect in endosperm function. Silencing of the paternal MEA allele in the endosperm and the phenotype of mutant mea seeds supports the parental conflict theory for the evolution of imprinting in plants and mammals.

Alleles↗

PubMed2004

Characterization of the imprinted polycomb gene L3MBTL, a candidate 20q tumour suppressor gene, in patients with myeloid malignancies.

Chromosome 20q deletion is a recurrent chromosomal abnormality associated with myeloid malignancies. L3MBTL represents a strong candidate tumour suppressor gene since it lies within the common deleted region, is a member of the Polycomb-like family, encodes the human homologue of a Drosophila tumour suppressor and is expressed within haematopoietic progenitor cells. We describe the structure of L3MBTL, identify two putative promoters each associated with two CpG islands and characterize a complex pattern of alternative splicing events. Mutation analysis of the gene in patients with and without a 20q deletion identified several polymorphisms but no acquired mutations. The two CpG islands spanning promoter 2 undergo monoallelic methylation in normal haematopoietic cells consistent with imprinting of L3MBTL. Samples from patients with a 20q deletion retained either the methylated or unmethylated allele but retention of the methylated allele did not correlate with reduction in L3MBTL mRNA levels. The absence of a correlation between L3MBTL methylation and transcription could be shown to reflect loss of imprinting in one patient. In addition, our results demonstrate that inactivation of L3MBTL is not a common occurrence in patients with a 20q deletion or in cytogenetically normal patients with polycythaemia vera.

Alternative Splicing↗

PubMed2004

FIE and CURLY LEAF polycomb proteins interact in the regulation of homeobox gene expression during sporophyte development.

The Arabidopsis FERTILIZATION-INDEPENDENT ENDOSPERM (FIE) polycomb group (PcG) protein, a WD40 homologue of Drosophila extra sex comb (ESC), regulates endosperm and embryo development and represses flowering during embryo and seedling development. As fie alleles are not transmitted maternally, homozygous mutant plants cannot be obtained. To study FIE function during the entire plant life cycle, we used Arabidopsis FIE co-suppressed plants. Low FIE level in these plants produced dramatic morphological aberrations, including loss of apical dominance, curled leaves, early flowering and homeotic conversion of leaves, flower organs and ovules into carpel-like structures. These morphological aberrations are similar to those exhibited by plants overexpressing AGAMOUS (AG) or CURLY LEAF (clf) mutants. Furthermore, the aberrant leaf morphology of FIE-silenced and clf plants correlates with de-repression of the class I KNOTTED-like homeobox (KNOX) genes including KNOTTED-like from Arabidopsis thaliana 2 (KNAT2) and SHOOTMERISTEMLESS (STM), whereas BREVIPEDICELLUS (BP) was upregulated in FIE-silenced plants, but not in the clf mutant. Thus, FIE is essential for the control of shoot and leaf development. Yeast two-hybrid and pull-down assays demonstrate that FIE interacts with CLF. Collectively, the morphological characteristics, together with the molecular and biochemical data presented in this work, strongly suggest that in plants, as in mammals and insects, PcG proteins control expression of homeobox genes. Our findings demonstrate that the versatility of the plant FIE function, which is derived from association with different SET (SU (VAR)3-9, E (Z), Trithorax) domain PcG proteins, results in differential regulation of gene expression throughout the plant life cycle.

Arabidopsis↗

PubMed2005

Polycomb group genes control developmental timing of endosperm.

Polycomb (PcG) group proteins form modular complexes, which maintain repressed transcriptional states of target genes across cell divisions. As PcG complexes provide a memory of cell fate, such proteins might control temporal aspects of development. Loss-of-function of any of the FERTILIZATION INDEPENDENT SEED (FIS) PcG genes perturbs endosperm development. In this report we provide a detailed analysis of the phenotype of fis endosperm development using molecular and cellular markers. Wild type (WT) endosperm development undergoes a series of four major developmental phases timed by successive synchronous nuclei division. In fis endosperm the transition from phase 1, marked by a synchronous mode of nuclei divisions to phase 2, corresponding to the establishment of three mitotic domains, is absent. Accordingly, the expression of seven markers of phase 1 and phase 2 is temporally perturbed. In spite of such changes, specific sequences of developmental events still take place as in the WT. Overall, fis mutations are heterochronic mutations that cause a temporal deregulation in the ontogenic sequence of endosperm development.

Arabidopsis↗