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At least 145 records · Page 8Linked to original sources
PubMed1998

Mammalian Polycomb group genes are categorized as a new type of early response gene induced by B-cell receptor cross-linking.

Polycomb group (PcG) genes were initially described in Drosophila melanogaster as regulators of the homeobox gene. Four mammalian homologues, mel-18, bmi-1, M33 and rae-28, are analyzed in this study. They not only regulate mammalian homeotic genes by analogy with their Drosophila counterparts, but also have some influence on the growth and differentiation of B lymphocytes. Here we report that these four mammalian PcG genes are rapidly induced after antigen-receptor cross-linking in B cells. Thus we would like to propose that mammalian PcG genes can be categorized as a new type of immediate early gene.

Animals↗
PubMed2002

Chemokine-mediated thymopoiesis is regulated by a mammalian Polycomb group gene, mel-18.

Multiple chemokines are made in the thymus, and they are likely to function in the fine control of cellular migration and regulation of thymic T cell development. Mice lacking the gene mel-18, a member of the mammalian Polycomb group genes, displayed impaired thymic T cell development. Here we report that expression of chemokine receptors CXCR4 and CCR9 are regulated by mel-18 and that CXCL12/SDF-1- and CCL25/TECK-mediated chemotactic activities are also affected by the loss of mel-18. In mel-18-/- mice, high expression of CXCR4 on CD4-CD8- cells might lead to trapping in the SDF-1 rich subcapsular region, while low expression of CCR9 on CD4+CD8+ cells might reduce cell migration to the medulla. Therefore, this member of the Polycomb group genes plays a role in thymic T cell migration and differentiation via the chemokine system.

Animals↗
PubMed2000

Identification and analysis of a third mouse Polycomb gene, MPc3.

A new mouse Polycomb (Pc) gene, MPc3, has been identified. The MPc3 protein contains the highly conserved chromodomain and carboxy-terminal COOH box of other known Pc proteins from diverse species. Like other Pc proteins, MPc3 physically interacts with the RING finger proteins RING1A and dinG/RING1B. MPc3 maps to the distal arm of mouse chromosome 11 (11E2), a region that contains other known Pc genes in addition to several disease loci that may be linked to abnormal Pc gene function.

Amino Acid Sequence↗
PubMed2001

[Maintenance of cellular memory by Polycomb group genes].

The Polycomb-group genes (PcG) encode a group of repressors well known for their function in stably maintaining the inactive expression patterns of key developmental regulators, including homeotic genes. PcG genes are structurally and functionally conserved in Drosophila and Mammalians, and some homologues have been found in worms, yeast and plants. Their products act through different complexes and at least one of these complexes seems to induce histone deacetylation. In Drosophila, building of PcG complexes depends on both protein-protein interactions and recognition near target genes of specific DNA sequences called Polycomb-group response element (PRE). Together with the counteracting trithorax-group proteins, PcG products establish a form of cellular memory by faithfully maintaining transcription states determined early in embryogenesis. Here, we discuss several aspects of PcG functions: the composition of the different complexes, the establishment and the transmission of silencing to subsequent cell generations as well as the subnuclear localisation of the PcG products.

Animals↗
PubMed2001

The Polycomb group--no longer an exclusive club?

Polycomb group (PcG) proteins maintain silencing at target loci in higher eukaryotes but recent evidence suggests that about half of these proteins are also required for maintenance of activation at homeotic loci. We suggest that PcG and trithorax group response elements should acquire a new name, 'maintenance elements', to reflect the dual function of regulatory elements that bind both groups of proteins. New data suggest that there might be a functional link between PcG repression and cell-cycle regulation.

Animals↗
PubMed2003

Gene repression by Polycomb group protein complexes: a distinct complex for every occasion?

Polycomb group (PcG) proteins play important roles in maintaining the repressed transcriptional state of genes. PcG proteins operate as part of Polycomb repressive complexes (PRCs). 'Core' PRCs have been purified that contain only a limited number of PcG proteins. In addition, many gene regulatory proteins have been identified to interact with PcG proteins. However, it remains subject to discussion whether these interactions are transient or whether the regulatory proteins are real components of PRCs. It has also become clear that the compositions of 'core' PRCs differ amongst cell types and that extensive changes in compositions occur during the embryonic development of cells. Because of these dynamic changes, we argue that speaking of a definitive core PRC can be misleading.

Animals↗
PubMed2001

Regulation of Th2 cell differentiation by mel-18, a mammalian polycomb group gene.

Polycomb group (PcG) gene products regulate homeobox gene expression in Drosophila and vertebrates and also cell cycle progression of immature lymphocytes. In a gene-disrupted mouse for polycomb group gene mel-18, mature peripheral T cells exhibited normal anti-TCR-induced proliferation; however, the production of Th2 cytokines (IL-4, IL-5, and IL-13) was significantly reduced, whereas production of IFNgamma was modestly enhanced. Th2 cell differentiation was impaired, and the defect was associated with decreased levels in demethylation of the IL-4 gene. Significantly, reduced GATA3 induction was demonstrated. In vivo antigen-induced IgG1 production and Nippostrongylus brasiliensis-induced eosinophilia were significantly affected, reflecting the deficit in Th2 cell differentiation. Thus, the PcG gene products play a critical role in the control of Th2 cell differentiation and Th2-dependent immune responses.

Animals↗
PubMed1998

The Drosophila Polycomb group gene pleiohomeotic encodes a DNA binding protein with homology to the transcription factor YY1.

Genes of the Polycomb group (PcG) of Drosophila encode proteins necessary for the maintenance of transcriptional repression of homeotic genes. PcG proteins are thought to act by binding as multiprotein complexes to DNA through Polycomb group response elements (PREs); however, specific DNA binding has not been demonstrated for any of the PcG proteins. We have identified a sequence-specific DNA binding protein that interacts with a PRE from the Drosophila engrailed gene. This protein (PHO) is a homolog of the ubiquitous mammalian transcription factor Yin Yang-1 and is encoded by pleiohomeotic, a known member of the PcG. We propose that PHO acts to anchor PcG protein complexes to DNA.

Amino Acid Sequence↗
PubMed1998

Male-to-female sex reversal in M33 mutant mice.

Polycomb genes in Drosophila maintain the repressed state of homeotic and other developmentally regulated genes by mediating changes in higher-order chromatin structure. M33, a mouse homologue of Polycomb, was isolated by means of the structural similarity of its chromodomain. The fifth exon of M33 contains a region of homology shared by Drosophila and Xenopus. In Drosophila, its deletion results in the loss of Polycomb function. Here we have disrupted M33 in mice by inserting a poly(A) capture-type neo(r) targeting vector into its fifth exon. More than half of the resultant M33cterm/M33cterm mutant mice died before weaning, and survivors showed male-to-female sex reversal. Formation of genital ridges was retarded in both XX and XY M33cterm/M33cterm embryos. Gonadal growth defects appeared near the time of expression of the Y-chromosome-specific Sry gene, suggesting that M33 deficiency may cause sex reversal by interfering with steps upstream of Sry. M33cterm/M33cterm mice may be a valuable model in which to test opposing views regarding sex determination.

Animals↗
PubMed2006

Variability in the expression of polycomb proteins in different normal and tumoral tissues. A pilot study using tissue microarrays.

In spite of the known function of polycomb group (PcG) genes in stem cell self-renewal, control of cellular proliferation and differentiation, its role in cancer pathogenesis is still poorly understood. We studied the expression by immunohistochemistry of several PcG-maintenance complex proteins (RING1, RNF2, BMI1, MEL18, HPH1 and RYBP) in nontumoral (154 samples) and tumoral (550 samples) human tissues using Tissue Microarrays. For selected genes (BMI1 and RING1) FISH analysis has been also carried out. PcG proteins had a tissue- and cell-type-specific expression pattern. Some of them were highly selectively expressed, such as HPH1, which was detected in germ cells in testis, pituitary and parathyroid glands and Langerhans islets, and RYBP, which was found in placenta, umbilical cord and thyroid gland. By contrast, RING1 was ubiquitously expressed in every normal tissue analyzed. Changes in expression associated with tumoral transformation have been found for BMI1 and RNF2, which exhibited increased expression in a large series of tumors, including gastrointestinal tumors, pituitary and parathyroid adenomas, and lymphomas, compared with their expression in normal-cell counterparts. The high level of expression of BMI1 protein observed in mantle-cell lymphomas and pituitary adenomas is associated in some cases with amplification of BMI1 locus. These findings imply that upregulation of BMI1 may constitute a malignancy marker in different types of cancer, mainly in lymphoid and endocrine tumors. RING1 was lost in a group of renal-cell carcinomas and testicular germ-cell tumors. Lastly, RYBP is anomalously expressed in Hodgkin's lymphomas and oligodendrogliomas, among others tumors. A significant finding of the study is the identification of unique PcG profiles for some tumors, such as testicular germ-cell tumors, which have high levels of HPH1 expression and loss of RING1 and/or BMI1; pituitary adenomas, which expressed every PcG protein analyzed; and clear-cell renal-cell carcinoma, which was the only tumor other than testicular germ-cell tumors that did not express RING1.

Carrier Proteins↗
PubMed2007

Polycomb silencing mechanisms and the management of genomic programmes.

Polycomb group complexes, which are known to regulate homeotic genes, have now been found to control hundreds of other genes in mammals and insects. First believed to progressively assemble and package chromatin, they are now thought to be localized, but induce a methylation mark on histone H3 over a broad chromatin domain. Recent progress has changed our view of how these complexes are recruited, and how they affect chromatin and repress gene activity. Polycomb complexes function as global enforcers of epigenetically repressed states, balanced by an antagonistic state that is mediated by Trithorax. These epigenetic states must be reprogrammed when cells become committed to differentiation.

Animals↗
PubMed2001

The polycomb protein MPc3 interacts with AF9, an MLL fusion partner in t(9;11)(p22;q23) acute leukemias.

Polycomb group (PcG) proteins assemble to form large multiprotein complexes involved in gene silencing. Evidence suggests that PcG complexes are heterogeneous with respect to both protein composition and specific function. MPc3 is a recently described mouse Polycomb (Pc) protein that shares structural homology with at least two other Pc proteins, M33 and MPc2. All three Pc proteins bind another PcG protein, RING1, through a conserved carboxy-terminal C-box motif. Here, data are presented demonstrating that MPc3 also interacts with AF9, a transcriptional activator implicated in the development of acute leukemias. The carboxy-terminus of AF9 is fused to the MLL protein in leukemias characterized by t(9;11)(p22;q23) chromosomal translocations. Importantly, it is the carboxy-terminus of AF9 to which MPc3 binds. The AF9 binding site of MPc3 maps to a central, non-conserved, region of the polypeptide sequence. In contrast to MPc3, data indicate that the Pc protein M33 does not interact with AF9. This finding suggests a potentially unique role for MPc3 in linking a PcG silencing complex to a transcriptional activator protein.

3T3 Cells↗
PubMed2004

Disruption of E2F signaling suppresses the INK4a-induced proliferative defect in M33-deficient mice.

Polycomb group (Pc-G) proteins associate to form large complexes that repress Hox genes, thereby imposing Hox gene expression pattern required for development. However, Pc-G proteins have a Hox-independent function in controlling cell proliferation. Here we show that embryonic fibroblasts derived from M33-deficient mice are impaired in the progression into the S phase of the cell cycle, as shown by a reduced rate of incorporation of bromodeoxyuridine. These cells have a senescent phenotype, associated to an abnormal accumulation of the cyclin-dependent kinase inhibitor p16INK4a protein. We demonstrate that this defect is bypassed in mutant embryonic fibroblasts expressing a transdominant negative form of the cell cycle controlling transcription factor E2F (E2F-DB). In addition, we show that the polycomb protein M33 controls critical expansion of B- and T-lymphocyte precursors. Together, our results emphasize M33-Polycomb protein function in cell cycle control.

Animals↗
PubMed2002

MBLR, a new RING finger protein resembling mammalian Polycomb gene products, is regulated by cell cycle-dependent phosphorylation.

BACKGROUND: The RING finger proteins function in a variety of fundamental cellular processes. The products of some members of the Polycomb group (PcG) bear ring finger domains and are defined as a subclass of RING finger proteins. Among them are Drosophila posterior sex combs and suppressor 2 of zeste, whose RING fingers are conserved in vertebrate PcG proteins Mel18 and Bmi1. RESULTS: We have identified a new mammalian RING finger protein, termed MBLR due to its structural similarity to Mel18 and Bmi1 (Mel18 and Bmi1-like RING finger protein). MBLR interacts with some PcG proteins: in vitro biochemical data support the idea of a direct interaction of MBLR's RING finger domain with Ring1B, which is highly homologous to one of the mammalian PcG genes, Ring1A. We also show that MBLR acts as a transcriptional repressor in transiently transfected cells, as is the case for other PcG proteins. Immunocytochemical analysis reveals that MBLR protein is localized in a fine-grained distribution throughout the nucleoplasm in interphase cultured cells and in a fainter diffuse cytoplasmic distribution in mitotic cells. In addition, we find that serine 32 of MBLR is specifically phosphorylated during mitosis, most likely by CDK7, a component of the basal transcriptional machinery. CONCLUSION: Similarities to previously defined PcG proteins suggest that MBLR should be included in the same subclass of RING finger proteins as Mel18 and Bmi1. Although the biological relevance of the cell cycle-related phosphorylation remains to be demonstrated, serine 32 phosphorylation could nevertheless be functionally important.

Amino Acid Sequence↗
PubMed2005

Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase.

X inactivation involves the stable silencing of one of the two X chromosomes in XX female mammals. Initiation of this process occurs during early development and involves Xist (X-inactive-specific transcript) RNA coating and the recruitment of Polycomb repressive complex (PRC) 2 and PRC1 proteins. This recruitment results in an inactive state that is initially labile but is further locked in by epigenetic marks such as DNA methylation, histone hypoacetylation, and MACROH2A deposition. Here, we report that the E3 ubiquitin ligase consisting of SPOP and CULLIN3 is able to ubiquitinate the Polycomb group protein BMI1 and the variant histone MACROH2A. We find that in addition to MACROH2A, PRC1 is recruited to the inactivated X chromosome in somatic cells in a highly dynamic, cell cycle-regulated manner. Importantly, RNAi-mediated knock-down of CULLIN3 or SPOP results in loss of MACROH2A1 from the inactivated X chromosome (Xi), leading to reactivation of the Xi in the presence of inhibitors of DNA methylation and histone deacetylation. Likewise, Xi reactivation is also seen on MacroH2A1 RNAi under these conditions. Hence, we propose that the PRC1 complex is involved in the maintenance of X chromosome inactivation in somatic cells. We further demonstrate that MACROH2A1 deposition is regulated by the CULLIN3/SPOP ligase complex and is actively involved in stable X inactivation, likely through the formation of an additional layer of epigenetic silencing.

Blotting, Western↗
PubMed2001

The E2F6 transcription factor is a component of the mammalian Bmi1-containing polycomb complex.

The E2F transcription factors play a key role in the regulation of cellular proliferation and terminal differentiation. E2F6 is the most recently identified and the least well understood member of the E2F family. It is only distantly related to the other E2Fs and lacks the sequences responsible for both transactivation and binding to the retinoblastoma protein. Consistent with this finding, E2F6 can behave as a dominant negative inhibitor of the other E2F family members. In this study, we continue to investigate the possible role(s) of E2F6 in vivo. We report the isolation of RYBP, a recently identified member of the mammalian polycomb complex, as an E2F6-interacting protein. Mapping studies indicate that RYBP binds within the known "repression domain" of E2F6. Moreover, we demonstrate that endogenous E2F6 and polycomb group proteins, including RYBP, Ring1, MEL-18, mph1, and the oncoprotein Bmi1, associate with one another. These findings suggest that the biological properties of E2F6 are mediated through its ability to recruit the polycomb transcriptional repressor complex.

Animals↗
PubMed2005

Structural organization of a Sex-comb-on-midleg/polyhomeotic copolymer.

The polycomb group proteins are required for the stable maintenance of gene repression patterns established during development. They function as part of large multiprotein complexes created via a multitude of protein-protein interaction domains. Here we examine the interaction between the SAM domains of the polycomb group proteins polyhomeotic (Ph) and Sex-comb-on-midleg (Scm). Previously we showed that Ph-SAM polymerizes as a helical structure. We find that Scm-SAM also polymerizes, and a crystal structure reveals an architecture similar to the Ph-SAM polymer. These results suggest that Ph-SAM and Scm-SAM form a copolymer. Binding affinity measurements between Scm-SAM and Ph-SAM subunits in different orientations indicate a preference for the formation of a single junction copolymer. To provide a model of the copolymer, we determined the structure of the Ph-SAM/Scm-SAM junction. Similar binding modes are observed in both homo- and heterocomplex formation with minimal change in helix axis direction at the polymer joint. The copolymer model suggests that polymeric Scm complexes could extend beyond the local domains of polymeric Ph complexes on chromatin, possibly playing a role in long range repression.

Amino Acid Sequence↗