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PubMed2000

Mutations in the FIE and MEA genes that encode interacting polycomb proteins cause parent-of-origin effects on seed development by distinct mechanisms.

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, which replicates to generate the endosperm, a tissue that supports embryo development. The FERTILIZATION-INDEPENDENT ENDOSPERM (FIE) and MEDEA (MEA) genes encode WD and SET domain polycomb proteins, respectively. In the absence of fertilization, a female gametophyte with a loss-of-function fie or mea allele initiates endosperm development without fertilization. fie and mea mutations also cause parent-of-origin effects, in which the wild-type maternal allele is essential and the paternal allele is dispensable for seed viability. Here, we show that FIE and MEA polycomb proteins interact physically, suggesting that the molecular partnership of WD and SET domain polycomb proteins has been conserved during the evolution of flowering plants. The overlapping expression patterns of FIE and MEA are consistent with their suppression of gene transcription and endosperm development in the central cell as well as their control of seed development after fertilization. Although FIE and MEA interact, differences in maternal versus paternal patterns of expression, as well as the effect of a recessive mutation in the DECREASE IN DNA METHYLATION1 (DDM1) gene on mutant allele transmission, indicate that fie and mea mutations cause parent-of-origin effects on seed development by distinct mechanisms.

Arabidopsis↗

PubMed2001

The iab-7 polycomb response element maps to a nucleosome-free region of chromatin and requires both GAGA and pleiohomeotic for silencing activity.

In the work reported here we have undertaken a functional dissection of a Polycomb response element (PRE) from the iab-7 cis-regulatory domain of the Drosophila melanogaster bithorax complex (BX-C). Previous studies mapped the iab-7 PRE to an 860-bp fragment located just distal to the Fab-7 boundary. Located within this fragment is an approximately 230-bp chromatin-specific nuclease-hypersensitive region called HS3. We have shown that HS3 is capable of functioning as a Polycomb-dependent silencer in vivo, inducing pairing-dependent silencing of a mini-white reporter. The HS3 sequence contains consensus binding sites for the GAGA factor, a protein implicated in the formation of nucleosome-free regions of chromatin, and Pleiohomeotic (Pho), a Polycomb group protein that is related to the mammalian transcription factor YY1. We show that GAGA and Pho interact with these sequences in vitro and that the consensus binding sites for the two proteins are critical for the silencing activity of the iab-7 PRE in vivo.

Amino Acid Motifs↗

PubMed2003

batman Interacts with polycomb and trithorax group genes and encodes a BTB/POZ protein that is included in a complex containing GAGA factor.

Polycomb and trithorax group genes maintain the appropriate repressed or activated state of homeotic gene expression throughout Drosophila melanogaster development. We have previously identified the batman gene as a Polycomb group candidate since its function is necessary for the repression of Sex combs reduced. However, our present genetic analysis indicates functions of batman in both activation and repression of homeotic genes. The 127-amino-acid Batman protein is almost reduced to a BTB/POZ domain, an evolutionary conserved protein-protein interaction domain found in a large protein family. We show that this domain is involved in the interaction between Batman and the DNA binding GAGA factor encoded by the Trithorax-like gene. The GAGA factor and Batman codistribute on polytene chromosomes, coimmunoprecipitate from nuclear embryonic and larval extracts, and interact in the yeast two-hybrid assay. Batman, together with the GAGA factor, binds to MHS-70, a 70-bp fragment of the bithoraxoid Polycomb response element. This binding, like that of the GAGA factor, requires the presence of d(GA)n sequences. Together, our results suggest that batman belongs to a subset of the Polycomb/trithorax group of genes that includes Trithorax-like, whose products are involved in both activation and repression of homeotic genes.

Amino Acid Sequence↗

PubMed2004

Interaction of Polycomb-group proteins controlling flowering in Arabidopsis.

In Arabidopsis, the EMBYRONIC FLOWER2 (EMF2), VERNALISATION2 (VRN2) and FERTILISATION INDEPENDENT ENDOSPERM2 (FIS2) genes encode related Polycomb-group (Pc-G) proteins. Their homologues in animals act together with other Pc-G proteins as part of a multimeric complex, Polycomb Repressive Complex 2 (PRC2), which functions as a histone methyltransferase. Despite similarities between the fis2 mutant phenotype and those of some other plant Pc-G members, it has remained unclear how the FIS2/EMF2/VRN2 class Pc-G genes interact with the others. We have identified a weak emf2 allele that reveals a novel phenotype with striking similarity to that of severe mutations in another Pc-G gene, CURLY LEAF (CLF), suggesting that the two genes may act in a common pathway. Consistent with this, we demonstrate that EMF2 and CLF interact genetically and that this reflects interaction of their protein products through two conserved motifs, the VEFS domain and the C5 domain. We show that the full function of CLF is masked by partial redundancy with a closely related gene, SWINGER (SWN), so that null clf mutants have a much less severe phenotype than emf2 mutants. Analysis in yeast further indicates a potential for the CLF and SWN proteins to interact with the other VEFS domain proteins VRN2 and FIS2. The functions of individual Pc-G members may therefore be broader than single mutant phenotypes reveal. We suggest that plants have Pc-G protein complexes similar to the Polycomb Repressive Complex2 (PRC2) of animals, but the duplication and subsequent diversification of components has given rise to different complexes with partially discrete functions.

Animals↗

PubMed2001

Recruitment of components of Polycomb Group chromatin complexes in Drosophila.

Polycomb Group complexes assemble at polycomb response elements (PREs) in vivo and silence genes in the surrounding chromatin. To study the recruitment of silencing complexes, we have targeted various Polycomb Group (PcG) proteins by fusing them to the LexA DNA binding domain. When LexA-PC, -PSC, -PH or -SU(Z)2 are targeted to a reporter gene, they recruit functional PcG-silencing complexes that recapitulate the silencing behavior of a PRE: silencing is sensitive to the state of activity of the target chromatin. When the target is transcriptionally active, silencing is not established but when the target is not active at syncytial blastoderm, it becomes silenced. The repressed state persists through embryonic development but cannot be maintained in larval imaginal discs even when the LexA-PcG fusion is constitutively expressed, suggesting a discontinuity in the mechanism of repression. These proteins also interact with other PC-containing complexes in embryonic nuclear extracts. In contrast LexA-PHO is neither able to silence nor to interact with PC-containing complexes. Analysis of pho mutant embryos and of PRE constructs whose PHO-binding sites are mutated suggests that, while PHO is important for silencing in imaginal discs, it is not necessary for embryonic PcG silencing.

Animals↗

PubMed2002

Extensive conservation of sequences and chromatin structures in the bxd polycomb response element among Drosophilid species.

The Polycomb Response Element (PRE) is the nucleation site for the Polycomb silencing complexes. The sequences responsible for the recruitment of the components of the Polycomb complex are not well understood. A comparison of the bxd PRE sequences from several different Drosophila species shows that some changes have occurred during phylogeny but large blocks of sequence are conserved after a divergence of some 60 million years. We compare the PRE sequences, the sites of some known PRE binding proteins, the conservation of DNasel hypersensitive sites and relate them to the sequence of the Ultrabithorax promoter which these PREs regulate.

Animals↗

PubMed2004

Hierarchical recruitment of polycomb group silencing complexes.

Polycomb group (PcG) proteins maintain the transcriptional silence of target genes through many cycles of cell division. Here, we provide evidence for the sequential binding of PcG proteins at a Polycomb response element (PRE) in proliferating cells in which the sequence-specific DNA binding Pho and Phol proteins directly recruit E(z)-containing complexes, which in turn methylate histone H3 at lysine 27 (H3mK27). This provides a tag that facilitates binding by a Pc-containing complex. In wing imaginal discs, these PcG proteins also are present at discrete locations at or downstream of the promoter of a silenced target gene, Ubx. E(z)-dependent H3mK27 is also present near the Ubx promoter and is needed for Pc binding. The location of E(z)- and Pc-containing complexes downstream of the Ubx transcription start site suggests that they may inhibit transcription by interfering with assembly of the preinitiation complex or by blocking transcription initiation or elongation.

Animals↗

PubMed2004

MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1.

Polycomb group (PcG) proteins form chromatin-associated, transcriptionally repressive complexes, which are critically involved in the control of cell proliferation and differentiation. Although the mechanisms involved in PcG-mediated repression are beginning to unravel, little is known about the regulation of PcG function. We showed previously that PcG complexes are phosphorylated in vivo, which regulates their association with chromatin. The nature of the responsible PcG kinases remained unknown. Here we present the novel finding that the PcG protein Bmi1 is phosphorylated by 3pK (MAPKAP kinase 3), a convergence point downstream of activated ERK and p38 signaling pathways and implicated in differentiation and developmental processes. We identified 3pK as an interaction partner of PcG proteins, in vitro and in vivo, by yeast two-hybrid interaction and co-immunoprecipitation, respectively. Activation or overexpression of 3pK resulted in phosphorylation of Bmi1 and other PcG members and their dissociation from chromatin. Phosphorylation and subsequent chromatin dissociation of PcG complexes were expected to result in de-repression of targets. One such reported Bmi1 target is the Cdkn2a/INK4A locus. Cells overexpressing 3pK showed PcG complex/chromatin dissociation and concomitant de-repression of p14(ARF), which was encoded by the Cdkn2a/INK4A locus. Thus, 3pK is a candidate regulator of phosphorylation-dependent PcG/chromatin interaction. We speculate that phosphorylation may not only affect chromatin association but, in addition, the function of individual complex members. Our findings linked for the first time MAPK signaling pathways to the Polycomb transcriptional memory system. This suggests a novel mechanism by which a silenced gene status can be modulated and implicates PcG-mediated repression as a dynamically controlled process.

Cell Line↗

PubMed1990

Interactions of Polycomb and trithorax with cis regulatory regions of Ultrabithorax during the development of Drosophila melanogaster.

The activity of the Ultrabithorax gene is continuously required during imaginal development to maintain the morphogenetic identity of the third thoracic segment of Drosophila. The spatial pattern of Ultrabithorax gene expression depends on certain cis regulatory regions and several trans regulatory genes. Amongst the latter the Polycomb gene is necessary to maintain Ultrabithorax repressed in cells where it was not initially activated and the trithorax gene is required for maintaining the expression of the gene where initially active. We have studied genetic interactions between several Ultrabithorax mutations in coding and cis regulatory regions in combination with Polycomb and trithorax mutations. Our results suggest that Polycomb and trithorax gene products do not interact with Ultrabithorax protein products but interact (directly or indirectly) with specific and discrete cis regulatory regions such as those where anterobithorax and postbithorax but not bithorax mutations map. We discuss possible mechanisms of these interactions.

Alleles↗

PubMed1993

Elements of the Drosophila bithorax complex that mediate repression by Polycomb group products.

The Polycomb (Pc) group genes encode repressors that restrict expression of homeotic genes to precise domains along the anterior-posterior (A-P) axis. We describe germ-line transformation constructs, containing portions of the bxd, iab-2, or iab-3 regulatory regions of the bithorax complex (BX-C), that are controlled by Pc group products in embryos. There are multiple BX-C elements that mediate Pc group control, which we call Pc group response elements (PREs), and they can work when removed from the normal BX-C context. These constructs are each regulated by the genes Polycomb (Pc), extra sex combs (esc), Enhancer of zeste (E[z]), polyhomeotic (ph), Polycomb-like (Pcl), Sex comb on midleg (Scm), Posterior sex combs (Psc), and Additional sex combs (Asx), consistent with multiple Pc group products acting together. Depending upon context, a PRE from the iab-3 region can restrict expression in different A-P positions. Thus, PREs are not specialized for particular parasegments, suggesting that Pc group products do not directly specify A-P boundaries of homeotic expression. Instead, the results support the idea that Pc group products provide stable memory or imprinting of boundaries which are initially specified by gap and pair-rule regulators.

Animals↗

PubMed1990

Clonal analysis of segmental and compartmental homoeotic transformations in polycomb mutants of Drosophila melanogaster.

We describe two new effects of Polycomb mutations on the determination of compartments in the wing of Drosophila. Ventral and posterior wing compartments are transformed partially to their dorsal and anterior counterparts. Although these new phenotypes are most strongly expressed in lethal pharate adults heteroallelic for Pc2 and a new allele PcT2, they are also found regularly but with low expressivity as dominant phenotypes of all the other Pc alleles we tested. Several different intersegmental homoeotic transformations caused by Polycomb have previously been described, leading to the hypothesis that Polycomb regulates the activity of certain selector genes normally active in specific segments. We now show that the degree of expression of the inter- and intrasegmental transformations are highly correlated in a range of different Pc genotypes, and that more than one determinative decision can be affected in a single compartment. This suggests that the wild-type Pc product may act as a general regulator of several different selector genes so as to influence both early embryonic and later determinative decisions in the imaginal discs. To test this idea we used clonal analysis to look at the effects of Pc on clonal restrictions at the dorsoventral and anterioposterior compartment boundaries, and its time of action with respect to each phenotype.

Alleles↗

PubMed2003

Finally, worm polycomb-like genes meet Hox regulation.

Polycomb and Trithorax group proteins have been shown to regulate Hox gene expression in flies and mammals, but not in worms. Two reports in this issue of Developmental Cell establish a first link between Polycomb-like genes and Hox gene regulation in C. elegans. However, sequence comparison indicates that these genes may not be homologous to the fly Polycomb genes, suggesting that independent gene recruitment occurred during nematode evolution.

Animals↗

PubMed2004

Imprinting of the human L3MBTL gene, a polycomb family member located in a region of chromosome 20 deleted in human myeloid malignancies.

L3MBTL encodes a member of the Polycomb family of proteins, which, together with Trithorax group proteins, is responsible for the coordinated regulation of patterns of gene activity. Members of the Polycomb family also regulate self renewal of normal and malignant hematopoietic stem cells. L3MBTL lies in a region of chromosome 20, deletion of which is associated with myeloid malignancies and represents a good candidate for a 20q target gene. However, mutations of L3MBTL have not been identified in patients with 20q deletions or in cytogenetically normal patients. Here we demonstrate that monoallelic methylation of two CpG islands correlates with transcriptional silencing of L3MBTL, and that L3MBTL transcription occurs from the paternally derived allele in five individuals from two families. Expression of the paternally derived allele was observed in multiple hematopoietic cell types as well as in bone marrow derived mesenchymal cells. Deletions of 20q associated with myeloid malignancies resulted in loss of either the unmethylated or methylated allele. Our results demonstrate that L3MBTL represents a previously undescribed imprinted locus, a vertebrate Polycomb group gene shown to be regulated by this mechanism, and has implications for the pathogenesis of myeloid malignancies associated with 20q deletions.

Alleles↗

PubMed1999

Control of fertilization-independent endosperm development by the MEDEA polycomb gene in Arabidopsis.

Higher plant reproduction is unique because 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, a tissue that supports embryo development. To understand mechanisms that initiate reproduction, we isolated a mutation in Arabidopsis, f644, that allows for replication of the central cell and subsequent endosperm development without fertilization. When mutant f644 egg and central cells are fertilized by wild-type sperm, embryo development is inhibited, and endosperm is overproduced. By using a map-based strategy, we cloned and sequenced the F644 gene and showed that it encodes a SET-domain polycomb protein. Subsequently, we found that F644 is identical to MEDEA (MEA), a gene whose maternal-derived allele is required for embryogenesis [Grossniklaus, U., Vielle-Calzada, J.-P., Hoeppner, M. A. & Gagliano, W. B. (1998) Science 280, 446-450]. Together, these results reveal functions for plant polycomb proteins in the suppression of central cell proliferation and endosperm development. We discuss models to explain how polycomb proteins function to suppress endosperm and promote embryo development.

Arabidopsis↗

PubMed2000

RET finger protein is a transcriptional repressor and interacts with enhancer of polycomb that has dual transcriptional functions.

RET finger protein (RFP) belongs to the large B-box RING finger protein family and is known to become oncogenic by fusion with RET tyrosine kinase. Although RFP is reported to be a nuclear protein that is present in the nuclear matrix, its function is largely unknown. Here we show that RFP interacts with Enhancer of Polycomb (EPC) and strongly represses the gene transcription. Yeast two-hybrid assays revealed that the coiled-coil domain of RFP was associated with the EPcA domain and the carboxyl-terminal region of EPC. In addition, both proteins were co-precipitated from the lysates of human cells and mostly colocalized in the nucleus. Using the luciferase reporter-gene assay, we found that they repress the gene transcription activity independent of the differences of enhancers and promoters used, although the repressive activity of RFP was much stronger than that of EPC. The coiled-coil domain of RFP and the carboxyl-terminal region of EPC were most important for the repressive activity of each protein, whereas the EPcA domain had the transcription activating ability that is unique as the Polycomb group protein function. These results suggested that RFP may be involved in the epigenetic gene silencing mechanism cooperating with Polycomb group proteins and that EPC is a unique molecule with both repressive and transactivating activities.

Amino Acid Sequence↗

PubMed1997

Altered cellular proliferation and mesoderm patterning in Polycomb-M33-deficient mice.

In Drosophila, the trithorax-group and the Polycomb-group genes are necessary to maintain the expression of the homeobox genes in the appropriate segments. Loss-of-function mutations in those groups of genes lead to misexpression of the homeotic genes resulting in segmental homeotic transformations. Recently, mouse homologues of the Polycomb-group genes were identified including M33, the murine counterpart of Polycomb. In this report, M33 was targeted in mice by homologous recombination in embryonic stem (ES) cells to assess its function during development. Homozygous M33 (-/-) mice show greatly retarded growth, homeotic transformations of the axial skeleton, sternal and limb malformations and a failure to expand in vitro of several cell types including lymphocytes and fibroblasts. In addition, M33 null mutant mice show an aggravation of the skeletal malformations when treated to RA at embryonic day 7.5, leading to the hypothesis that, during development, the M33 gene might play a role in defining access to retinoic acid response elements localised in the regulatory regions of several Hox genes.

Animals↗

PubMed2003

Polycomb group proteins ESC and E(Z) are present in multiple distinct complexes that undergo dynamic changes during development.

The Polycomb Group proteins are required for stable long-term maintenance of transcriptionally repressed states. Two distinct Polycomb Group complexes have been identified, a 2-MDa PRC1 complex and a 600-kDa complex containing the ESC and E(Z) proteins together with the histone deacetylase RPD3 and the histone-binding protein p55. We report here that there are at least two embryonic ESC/E(Z) complexes that undergo dynamic changes during development and a third larval E(Z) complex that forms after disappearance of ESC. We have identified a larger embryonic ESC complex containing RPD3 and p55, along with E(Z), that is present only until mid-embryogenesis, while the previously identified 600-kDa ESC/E(Z) complex persists until the end of embryogenesis. Constitutive overexpression of ESC does not promote abnormal persistence of the larger or smaller embryonic complexes and does not delay a dissociation of E(Z) from the smaller ESC complex or delay appearance of the larval E(Z) complex, indicating that these changes are developmentally programmed and not regulated by the temporal profile of ESC itself. Genetic removal of ESC prevents appearance of E(Z) in the smaller embryonic complex, but does not appear to affect formation of the large embryonic ESC complex or the PRC1 complex. We also show that the ESC complex is already bound to chromosomes in preblastoderm embryos and present genetic evidence that ESC is required during this very early period.

Animals↗

PubMed1999

Cellular memory of transcriptional states by Polycomb-group proteins.

The Polycomb-group constitutes an important, widely conserved group of transcriptional repressors best known for their function in stably maintaining the inactive expression patterns of key developmental regulators, including homeotic genes. Together with the counteracting trithorax-group proteins, they establish a form of cellular memory by faithfully maintaining transcription states determined early in embryogenesis. Besides being crucial for the correct execution of developmental programs, Polycomb-group mediated silencing also appears to be involved in controlling cell proliferation. Here we discuss several aspects of Pc-G function: target gene specificity and recognition as well as propagation of inactive chromatin states to subsequent cell generations.

Animals↗