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PubMed2006

Noncoding RNA synthesis and loss of Polycomb group repression accompanies the colinear activation of the human HOXA cluster.

The ratio of noncoding to protein coding DNA rises with the complexity of the organism, culminating in nearly 99% of nonprotein coding DNA in humans. Nevertheless, a large portion of these regions is transcribed, creating the alleged paradox that noncoding RNA (ncRNA) represents the largest output of the human genome. Such a complex scenario may include epigenetic mechanisms where ncRNAs would be involved in chromatin regulation. We have investigated the intergenic, noncoding transcriptomes of mammalian HOX clusters. We show that "opposite strand transcription" from the intergenic spacer regions in the human HOXA cluster correlates with the activity state of adjacent HOXA genes. This noncoding transcription is regulated by the retinoic acid morphogen and follows the colinear activation pattern of the cluster. Opening of the cluster at sites of activation of intergenic transcripts is accompanied by changes in histone modifications and a loss of interaction with Polycomb group (PcG) repressive complexes. We propose that noncoding transcription is of fundamental importance for the opening and maintenance of the active state of HOX clusters.

Animals↗

PubMed2005

Control of reproduction by Polycomb Group complexes in animals and plants.

In both mammals and plants, Polycomb Repressive Complexes 2 (PRC2) are conserved and appear to be involved in the transition between vegetative or somatic and reproductive state in plants and mammals. In plants at least three different PRC2 control temporal aspects of development, and mutations in PcG cause heterochronies. Such heterochronic mutations affect the transition to flowering. During gametogenesis the Fertilization-Independent Endosperm-MEDEA-PRC2 (FIE-MEA PRC2) complex controls gametogenesis in synergy with a Retinoblastoma-dependent pathway. Several genes of the FIE-MEA pathway are imprinted as shown by their uniparental allele expression in the endosperm, the interface controlling maternal nutrition of the embryo in the seed. Imprinting is also a major feature for genes expressed in the placenta in mammals. Recent data have shown that imprinting in both placenta and endosperm likely share similar mechanisms involving cooperation between the PRC2 complexes and DNA methylation.

Animals↗

PubMed2005

Expression of Polycomb-group genes in human ovarian follicles, oocytes and preimplantation embryos.

Mammalian oocytes possess unique properties with respect to their ability to regulate and reprogram chromatin structure and epigenetic information. Proteins containing the conserved chromodomain motif that is common to the Polycomb-group (Pc-G) proteins and the heterochromatin-associated protein HP1, play essential roles in these processes and more specifically, in X-chromosome inactivation in female zygotes and extra-embryonic tissues and in the regulation of genomic imprinting. To characterize the potential role of these proteins in the regulation of epigenetic events during early human development, we utilized a degenerate PCR priming assay to assess the expression of mRNAs of chromodomain proteins in cDNA samples derived from the human female germline and preimplantation embryos. Expression of mRNAs of HP1 genes was observed in ovarian follicles, (HP1 (HSalpha), HP1 (HSbeta), HP1 (HSgamma)), mature oocytes (HP1 (HSalpha), HP1 (HSbeta)), cleavage stage preimplantation embryos (HP1 (HSalpha), HP1 (HSbeta), HP1 (HSgamma)) and blastocysts (HP1 (HSalpha), HP1 (HSgamma)). Transcripts for three Pc-G genes, which are essential for early mammalian development (Yin Yang 1 (YY1), Enhancer of Zeste-2 (EZH2) and Embryonic Ectoderm Development (EED)) and that are essential for the regulation of X-inactivation and certain imprinted genes (EED) were revealed by gene-specific-PCR expression analysis of human ovarian follicles, oocytes and preimplantation embryos. YY1 and EZH2 transcripts were additionally detected in metaphase II oocytes.

Base Sequence↗

PubMed2005

Epigenetic regulation of hematopoietic stem cell self-renewal by polycomb group genes.

Polycomb group (PcG) genes are involved in the maintenance of cellular memory through epigenetic chromatin modifications. Recent studies have implicated a role for PcG genes in the self-renewal of hematopoietic stem cells (HSCs), a process in which cellular memory is maintained through cell division. Among the PcG genes, Bmi-1 plays a central role in the inheritance of stemness, and its forced expression promotes HSC self-renewal. These findings highlight the importance of epigenetic regulation in HSC self-renewal and identify PcG genes as potential targets for therapeutic HSC manipulation.

Apoptosis↗

PubMed2005

Of mice, flies, and man: the emerging role of polycomb-group genes in human malignant lymphomas.

Genes belonging to the Polycomb group (PcG) are responsible for the maintenance of cell identity and are directly involved in epigenetic gene silencing. They perform a vital role in the regulation of embryogenesis but also contribute to various adult processes, including regulation of the cell cycle and lymphopoiesis. Experimental model systems have demonstrated that enhanced expression of individual PcG genes, such as Bmi1, results in the development of B-cell and T-cell lymphomas. In humans, a growing body of work has now linked human PcG genes to various hematologic and epithelial cancers. This review focuses on the emerging role of PcG genes in the development of human malignant lymphomas.

Animals↗

PubMed2004

A mosaic genetic screen reveals distinct roles for trithorax and polycomb group genes in Drosophila eye development.

The wave of differentiation that traverses the Drosophila eye disc requires rapid transitions in gene expression that are controlled by a number of signaling molecules also required in other developmental processes. We have used a mosaic genetic screen to systematically identify autosomal genes required for the normal pattern of photoreceptor differentiation, independent of their requirements for viability. In addition to genes known to be important for eye development and to known and novel components of the Hedgehog, Decapentaplegic, Wingless, Epidermal growth factor receptor, and Notch signaling pathways, we identified several members of the Polycomb and trithorax classes of genes encoding general transcriptional regulators. Mutations in these genes disrupt the transitions between zones along the anterior-posterior axis of the eye disc that express different combinations of transcription factors. Different trithorax group genes have very different mutant phenotypes, indicating that target genes differ in their requirements for chromatin remodeling, histone modification, and coactivation factors.

Animals↗

PubMed2005

The Polycomb group protein EZH2 impairs DNA repair in breast epithelial cells.

The Polycomb group protein EZH2 is a transcriptional repressor involved in controlling cellular memory and has been linked to aggressive and metastatic breast cancer. Here we report that EZH2 decreased the expression of five RAD51 paralog proteins involved in homologous recombination (HR) repair of DNA double-strand breaks (RAD51B/RAD51L1, RAD51C/RAD51L2, RAD51D/RAD51L3, XRCC2, and XRCC3), but did not affect the levels of DMC1, a gene that only functions in meiosis. EZH2 overexpression impaired the formation of RAD51 repair foci at sites of DNA breaks. Overexpression of EZH2 resulted in decreased cell survival and clonogenic capacity following DNA damage induced independently by etoposide and ionizing radiation. We suggest that EZH2 may contribute to breast tumorigenesis by specific downregulation of RAD51-like proteins and by impairment of HR repair. We provide mechanistic insights into the function of EZH2 in mammalian cells and uncover a link between EZH2, a regulator of homeotic gene expression, and HR DNA repair. Our study paves the way for exploring the blockade of EZH2 overexpression as a novel approach for the prevention and treatment of breast cancer.

Breast↗

PubMed2006

Regulation of Th2 cell development by Polycomb group gene bmi-1 through the stabilization of GATA3.

The Polycomb group (PcG) gene products regulate the maintenance of the homeobox gene expression in Drosophila and vertebrates and also the cell cycle progression in thymocytes and Th2 cell differentiation in mature T cells. We herein studied the role of PcG gene bmi-1 product in Th1/Th2 cell differentiation and found that Bmi-1 facilitates Th2 cell differentiation in a Ring finger-dependent manner. Biochemical studies indicate that Bmi-1 interacts with GATA3 in T cells, which is dependent on the Ring finger of Bmi-1. The overexpression of Bmi-1 resulted in a decreased ubiquitination and an increased protein stability of GATA3. In bmi-1-deficient Th cells, the levels of Th2 cell differentiation decreased as the degradation and ubiquitination on GATA3 increased. Therefore, Bmi-1 plays a crucial role in the control of Th2 cell differentiation in a Ring finger-dependent manner by regulating GATA3 protein stability.

Animals↗

PubMed2006

The role of polycomb group proteins in cell cycle regulation during development.

Polycomb group (PcG) and trithorax group (trxG) proteins are evolutionarily conserved chromatin modifiers that have well known roles in the maintenance of silent and active expression states of homeotic genes. PcG proteins may also be involved in the control of cellular proliferation, as several PcG complexes have been shown to act either as proto-oncogenes or as tumor suppressors in vertebrates. In Drosophila, PcG factors associate with specific DNA regions termed PcG response elements (PREs), and a PRE was recently identified in the gene encoding Cyclin A. Still, it is not yet clear how PcG complexes could control cell cycle progression. Beyond acting as stable silencers of cell cycle genes during the differentiation process, PcG complexes might also be integrators and/or modulators of cell cycle checkpoints in dividing cells. Here, we discuss this dual aspect of PcG involvement in epigenetic cell cycle control.

Animals↗

PubMed2006

Genomic models of metastatic cancer: functional analysis of death-from-cancer signature genes reveals aneuploid, anoikis-resistant, metastasis-enabling phenotype with altered cell cycle control and activated Polycomb Group (PcG) protein chromatin silencing pathway.

A recent discovery of death-from-cancer signature genes identifies potential markers predicting the high likelihood of treatment failure in cancer patients. This knowledge provides the opportunity to analyze in functional terms the therapy-resistant and metastasis-enabling phenotypes of cancer cells. Here we summarize the current data regarding the biological functions of genes comprising a death-from-cancer signature. This analysis predicts that cancer cells manifesting a stem cell-like expression profile of a death-from-cancer signature would exhibit the following features: a concomitantly increased expression of certain members of inhibitor of apoptosis protein (IAP) family (Survivin and XIAP); activation of mitotic spindle check point proteins (BUB1, BUB3, KNTC2, Mad2, PLK1, PLK4, STK6/Aurora A); and elevated levels of certain cell cycle control/marker proteins (CCNB1, CCNB2, CCND1, CCNA2, CDC2, CDC25, Ki67, USP22). Consequently, these cancer cells would acquire metastasis-enabling anoikis-resistance aneuploid phenotype with aberrant cell cycle control. A functionally complementary role of multiple cooperating oncogenic pathways and the essential role of Polycomb Group (PcG) protein chromatin silencing pathway in emergence of the stem cell cancer phenotype is highlighted.

Aneuploidy↗

PubMed2006

Stem cells primed for action: polycomb repressive complexes restrain the expression of lineage-specific regulators in embryonic stem cells.

Stem cells are characterised by a capacity to self renew and generate progeny capable of differentiating along several defined lineage paths. Embryonic Stem (ES) cells are derived from the inner cell mass (ICM) of early-stage embryos and can contribute to all tissues of the developing embryo. Discovering how ES cell pluripotency and lineage induction is achieved is important for understanding normal development and for successfully applying stem cell-based therapies. A series of recent studies have shown that the chromatin profile of ES cells is unusual and have revealed a critical role for the Polycomb Repressive Complexes (PRCs) in maintaining pluripotency. In human and mouse ES cells many genes that encode transcription factors that are required for lineage specification bind PRC2 and carry bivalent (or opposing) histone signatures, being enriched for conventional indicators of active chromatin such as acetylated H3K9 and methylated H3K4, while lying within domains of repressive trimethylated H3K27. Mutant ES cells that lack H3K27 methylation inappropriately expressed these genes showing that PRC2 represses lineage-specific gene programs in ES cells. Here we discuss the implications of these new discoveries and explore the interdependence of PRC1 and PRC2 in regulating lineage-specific gene expression in ES cells.

Animals↗

PubMed2005

A unified mode of epigenetic gene silencing: RNA meets polycomb group proteins.

Recently, an essential role for RNA in the epigenetic silencing of genes packaged within heterochromatin in animals has been recognized. The RNA appears to be involved in targeting chromatin remodeling activity to a specific locus and in later maintaining the repressed state of the gene. Epigenetic silencing of Hox cluster genes by the Polycomb group proteins also involves the formation of a stably inherited repressive chromatin structure. Recent studies of the C. elegans PcG gene sop-2 reveled an evolutionarily conserved property of PcG proteins in the binding of RNA, suggesting an important role for RNA in PcG-mediated Hox gene repression.

Animals↗

PubMed2005

Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas.

The polycomb group protein enhancer of zeste 2 (EZH2) is a transcriptional repressor involved in the control of cellular proliferation and oncogenesis. The aim of the present study was to quantify EZH2 expression in bladder carcinomas and to correlate the data with clinicopathological findings. EZH2 mRNA expression was measured by real-time reverse transcription-polymerase chain reaction in tumor tissue specimens obtained from 37 patients with urothelial carcinomas of the bladder and in four bladder cancer cell lines. EZH2 levels were normalized to expression of the housekeeping porphobilinogen deaminase gene. EZH2 transcripts were commonly detected in tumor tissue. Transcript levels correlated significantly with the invasiveness of bladder tumors (p = 0.029) with elevated EZH2 mRNA expression measured in invasive bladder carcinomas (median value, 38.92) compared with non-invasive tumors (15.51). In addition, levels of expression were significantly higher in high-grade (G3) than in low-grade (G1/2) lesions (p < 0.001). EZH2 mRNA levels in bladder carcinoma cell lines were within the range of high-grade invasive bladder cancers. In conclusion, expression levels of EZH2 are elevated in aggressive and invasive urothelial carcinomas, suggesting that deregulated EZH2 expression may be involved in the progression of bladder tumors.

Aged↗

PubMed2002

Role for O-glycosylation of RFP in the interaction with enhancer of polycomb.

We recently demonstrated that RFP, which belongs to the large B-box RING finger protein family, interacts with Enhancer of Polycomb 1 (EPC1) and functions as a transcriptional repressor in human cultured cells. In this study, we examined the expression of RFP and EPC1 in mouse tissues by immunoblotting as well as their interaction by a pull-down assay. Both RFP and EPC1 proteins are expressed in several mouse tissues including testis, spleen, thymus, adrenal gland, cerebrum, and cerebellum. In addition, they were coprecipitated from the lysate of mouse testis. Pull-down assays using glutathione S-transferase (GST)-fused EPC1 proteins revealed that RFP is associated with the EPcA, EPcB, and carboxy-terminal (CT) regions of EPC1. Although RFP is highly expressed as 58- and 68-kDa proteins in mouse testis, the EPC1 CT region more strongly interacted with the 68-kDa form than the EPcA or EPcB region. Interaction of the 58-kDa form of RFP with each region was weak compared with that of the 68-kDa form with the EPC1 CT region. Because the 68-kDa form of RFP was almost completely digested with O-glycosidase but not with N-glycosidase, this suggested that O-glycosylation of RFP plays a role in its interaction with the EPC1 CT region that may be responsible for transcriptional repression. In addition, the luciferase reporter gene assay showed that expression of the EPcA region strongly impairs the transcriptional repressive activity of RFP.

Adrenal Glands↗

PubMed1994

Mutations in some Polycomb group genes of Drosophila interfere with regulation of segmentation genes.

Mutations in several Polycomb (Pc) group genes cause maternal-effect or zygotic segmentation defects, suggesting that Pc group genes may regulate the segmentation genes of Drosophila. We show that individuals doubly heterozygous for mutations in polyhomeotic and six other Pc group genes show gap, pair rule, and segment polarity segmentation defects. We examined double heterozygous combinations of Pc group and segmentation mutations for enhancement of adult and embryonic segmentation defects. Posterior sex combs and polyhomeotic interact with Krüppel and enhance embryonic phenotypes of hunchback and knirps, and polyhomeotic enhances even-skipped. Surprisingly, flies carrying duplications of extra sex combs (esc), that were heterozygous for mutations of even-skipped (eve), were extremely subvital. Embryos and surviving adults of this genotype showed strong segmentation defects in even-numbered segments. Antibody studies confirm that expression of eve is suppressed by duplications of esc. However, esc duplications have no effect on other gap or pair rule genes tested. To our knowledge, this is only the second triplo-abnormal phenotype associated with Pc group genes. Duplications of nine other Pc group genes have no detectable effect on eve. Expression of engrailed (en) was abnormal in the central nervous systems of most Pc group mutants. These results support a role for Pc genes in regulation of some segmentation genes, and suggest that esc may act differently from other Pc group genes.

Abdomen↗

PubMed1983

The maternal and zygotic roles of the gene Polycomb in embryonic determination in Drosophila melanogaster.

The mutation Polycomb (Pc) is known to cause a variety of intersegmental transformations in homozygous and heterozygous individuals of Drosophila melanogaster; Pc+ is thought to act as a negative regulator of genes of the bithorax complex. The function of this gene in the maternal germ line has been assessed by examining the variation in expression of these homoeotic phenotypes in individuals derived from a maternal germ line with a single or no dose of the Pc+ allele. Mosaic individuals with a homozygous or heterozygous Pc germ line were produced by transplantation of pole cells, the embryonic precursors of the germ line. By employing an X-linked dominant female-sterile mutation, the identification of mosaic females and the study of progeny derived from the exogenous germ line were greatly simplified; the advantages of this system for the transplantation of pole cells for such analyses are described. In general, all thoracic and abdominal segments of homozygous Pc embryos differentiate characteristics of the eighth, most posterior, abdominal segment. The extent and uniformity of this transformation as well as other manifestations of the homozygous Pc genotype are described and shown to be correlated with the maternal germ line genotype; homozygous Pc embryos derived from a homozygous Pc maternal germ line show greater expression of these phenotypes than do genetically identical embryos derived from a heterozygous Pc maternal germ line. The expression of some homoeotic phenotypes typical of heterozygous Pc adults shows only a slight correlation with the maternal genotype, while no homoeotic transformations are clearly evident in heterozygous larvae of either origin. Thus, the maternal effect of Pc is rescuable. The results suggest that the Pc+ gene is active in the maternal germ line but that the absence of the maternally derived Pc+ product can be largely compensated by the introduction of a wild-type allele upon fertilization; this rescue indicates that the maternal activity of Pc+ plays no major role in the normal process of embryonic segmental determination. The normal fertility of males and females with a homozygous Pc germ line and of their progeny suggests that Pc+ plays no role in the determination or development of the germ line in either the maternal or zygotic genome.

Alleles↗

PubMed1986

Spatial regulation of Antennapedia and bithorax gene expression by the Polycomb locus in Drosophila.

Transcripts encoded by six of the homeotic lethal complementation groups within the Antennapedia and bithorax gene complexes (ANT-C and BX-C) accumulate primarily in nonoverlapping regions of the embryonic central nervous system (CNS). It has been previously proposed that the maintenance of these selective patterns of expression involve hierarchical cross-regulatory interactions among ANT-C and BX-C loci. Selective expression of the ANT-C and BX-C also involves regulation by a number of unlinked genetic loci, including the Polycomb (Pc) locus. Here we show that the ANT-C and BX-C transcript distribution patterns are dramatically altered in the CNS of Pc- embryos. We discuss these altered patterns of expression in the context of different models for the spatial regulation of ANT-C and BX-C gene expression.

Animals↗

PubMed1994

Imaginal disc silencers from Ultrabithorax: evidence for Polycomb response elements.

Silencers from the Drosophila homeotic gene Ultrabithorax (Ubx) require hunchback (hb) and Polycomb (Pc) to suppress the activity of embryonic enhancers outside the Ubx domain. Embryonic silencing is initiated by hb protein which binds to the silencers to repress Ubx, thereby defining the Ubx domain. Here, we study silencing during subsequent development by examining expression patterns in imaginal discs conferred by individual Ubx fragments and pair-wise combinations thereof. We find that fragments which mediate silencing in anterior regions of imaginal discs contain embryonic silencers and hb target sites. One exception to this is a fragment called BXD which is not under hb control itself, but whose silencing activity depends on combination with fragments containing hb protein binding sites. Since silencing by BXD also requires Pc function, this suggests that BXD contains target sites for Pc or for Pc-like proteins. We propose that stable silencing of Ubx is achieved through cooperation between hb and Pc target sites.

Animals↗