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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↗

PubMed1996

The Drosophila Polycomb group gene Sex comb on midleg (Scm) encodes a zinc finger protein with similarity to polyhomeotic protein.

The Sex comb on midleg (Scm) gene is a member of the Polycomb group (PcG) of genes in Drosophila melanogaster. The PcG genes encode transcriptional repressors required for proper spatial expression of homeotic genes. We report the isolation of new Scm mutations and the molecular characterization of the Scm gene. Scm mRNA is expressed maternally, at peak levels in early embryos and then at lower levels throughout the remainder of development. Scm encodes a putative zinc finger protein of 877 amino acids. Scm protein is similar to polyhomeotic, another member of the PcG, both in the zinc finger region and in a separate C-terminal domain of 60 amino acids, which we term the SPM domain. Sequence analysis of an Scm mutant allele suggests a functional requirement for the SPM domain. Scm protein also bears homology in multiple domains to a mouse protein, Rae-28 (Nomura, M., Takihara, Y. and Shimada, K. (1994) Differentiation 57,39-50) and to a fly tumor suppressor protein, the product of the lethal(3)malignant brain tumor gene (Wismar, J. et al., (1995) Mech. Dev. 53, 141-154). Possible functional relationships among these proteins and potential biochemical roles for Scm protein in PcG repression are discussed.

Amino Acid Sequence↗

PubMed2000

Loss- and gain-of-function mutations show a polycomb group function for Ring1A in mice.

The products of the Polycomb group (PcG) of genes act as transcriptional repressors involved in the maintenance of homeotic gene expression patterns throughout development, from flies to mice. Biochemical and molecular evidence suggests that the mouse Ring1A gene is a member of the PcG of genes. However, genetic evidence is needed to establish PcG function for Ring1A, since contrary to all other murine PcG genes, there is no known Drosophila PcG gene encoding a homolog of the Ring1A protein. To study Ring1A function we have generated a mouse line lacking Ring1A and mouse lines overexpressing Ring1A. Both Ring1A(-/-)and Ring1A(+/-) mice show anterior transformations and other abnormalities of the axial skeleton, which indicates an unusual sensitivity of axial skeleton patterning to Ring1A gene dosage. Ectopic expression of Ring1A also results in dose-dependent anterior transformations of vertebral identity, many of which, interestingly, are shared by Ring1A(-/-) mice. In contrast, the alterations of Hox gene expression observed in both type of mutant mice are subtle and involve a reduced number of Hox genes. Taken together, these results provide genetic evidence for a PcG function of the mouse Ring1A gene.

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↗

PubMed2003

Polycomb group gene silencing proteins are concentrated in the perichromatin compartment of the mammalian nucleus.

Human Polycomb group (PcG) proteins are involved in cell-type-dependent epigenetic gene silencing in an evolutionarily conserved manner. We have analysed the subnuclear localisation of these regulatory proteins in two different human cell lines and in rat liver tissue by means of light and electron immunomicroscopy using specific antibodies. We find that the PcG proteins HPC2, HPH1, BMI1 and RING1 are highly concentrated in the perichromatin compartment, situated at the surface of condensed chromatin domains. This compartment was demonstrated earlier to be the nuclear site where most pre-mRNA synthesis takes place. Interestingly, these PcG proteins are virtually absent from the interior of condensed chromatin areas. The present observations therefore show that transcriptionally active and PcG-silenced loci occur within the same spatially limited nuclear domain. Our novel high-resolution data strongly support the idea that epigenetic PcG-mediated gene silencing is a local event, rather than affecting large chromatin domains. In addition to being associated with the perichromatin region, PcG proteins also occur in the interchromatin space. Implications of these observations for higher order chromatin structure and for the mechanisms of PcG-mediated gene silencing are discussed.

Animals↗

PubMedDate not supplied

Increased expression of the EZH2 polycomb group gene in BMI-1-positive neoplastic cells during bronchial carcinogenesis.

Polycomb group (PcG) genes are responsible for maintenance of cellular identity and contribute to regulation of the cell cycle. Recent studies have identified several PcG genes as oncogenes, and a role for PcG proteins in human oncogenesis is suspected. We investigated the expression of BMI-1 and EZH2 PcG oncogenes in human bronchial squamous cell carcinomas (SCCs) and bronchial premalignant precursor lesions (PLs). Whereas normal bronchial epithelium was associated with widespread expression of BMI-1 in resting EZH2-negative cells, neoplastic cells in lung carcinomas displayed altered expression of both BMI-1 and EZH2. Two patterns of abnormal PcG expression were observed: increased expression of BMI-1 in dividing neoplastic cells of PLs and SCCs, and enhanced expression of EZH2 and Ki-67 in BMI-1-positive cells according to severity of the histopathologic stage. We propose that altered expression of BMI-1 and EZH2 is an early event that precedes high rates of proliferation in lung cancer. Because PcG complexes are normally involved in the maintenance of cell characteristics, abnormal PcG expression may contribute to loss of cell identity.

Aged↗

PubMed2006

Identification of a nuclear localization signal in mouse polycomb protein, M33.

The mouse Polycomb group (PcG) protein M33 forms nuclear complexes with the products of other PcG members and maintains repressed states of developmentally important genes, including homeotic genes. In this context, nuclear localization is a prerequisite for M33 to exert its function. However, we previously found that M33 in mouse liver shuttles dynamically between the nucleus and the cytoplasm, depending on the proliferative states of cells, coupled with phosphorylation and dephosphorylation of M33 protein. To understand the mechanism and significance of this phenomenon, we identified the functional nuclear localization signal (NLS) of M33 protein. Deletion mutants that lack a particular one of three putative NLS motifs failed to localize in the nucleus. Green fluorescent protein (GFP) fused to this motif specifically localized in the nucleus. We conclude that this amino-acid stretch in M33 acts as the functional NLS for this protein.

Animals↗

PubMed2005

Polycomb group gene mel-18 regulates early T progenitor expansion by maintaining the expression of Hes-1, a target of the Notch pathway.

Polycomb group (PcG) proteins play a role in the maintenance of cellular identity throughout many rounds of cell division through the regulation of gene expression. In this report we demonstrate that the loss of the PcG gene mel-18 impairs the expansion of the most immature T progenitor cells at a stage before the rearrangement of the TCR beta-chain gene in vivo and in vitro. This impairment of these T progenitors appears to be associated with increased susceptibility to cell death. We also show that the expression of Hes-1, one of the target genes of the Notch signaling pathway, is drastically down-regulated in early T progenitors isolated from mel-18(-/-) mice. In addition, mel-18(-/-) T precursors could not maintain the Hes-1 expression induced by Delta-like-1 in monolayer culture. Collectively, these data indicate that mel-18 contributes to the maintenance of the active state of the Hes-1 gene as a cellular memory system, thereby supporting the expansion of early T progenitors.

Animals↗

PubMed2000

Polycomb-group genes and hematopoiesis.

Although long-range chromatin organization during cell differentiation has not yet been determined, considerable evidence suggests that regulation of the chromatin structure may play a crucial part in transcriptional regulation. Drosophila genetics has introduced a unique system that can maintain genes in the on or off state after the initial gene expression decision has been established. This maintenance system is known to be mediated through the trithorax-group (trxG) and Polycomb-group (PcG) genes. The products from these 2 genes individually form multimeric complexes in the chromatin. The trxG genes are known to maintain the transcriptionally active states of the chromatin, and the PcG genes are thought to maintain the repressive states. The function of the PcG genes is defined in terms of anteroposterior patterning not only in Drosophila but also in mammals, whereas mammalian PcG genes have additional functions in higher order biological functions All PcG gene-deficient mice have provided evidence that these genes play a crucial role in hematopoiesis These findings should help shed new light on the roles of the chromatin regulatory system in hematopoiesis.

Animals↗

PubMed2004

Polycomb group proteins in cell cycle progression and cancer.

Epigenetic deregulation of gene expression is emerging as key mechanism in tumorigenesis. Deregulated activity of the chromatin remodeling Polycomb Repressive Complex 2 (PRC2) has recently been shown to be a frequent event in human tumors. Here we discuss these findings and speculate on the role of the PRC2 complex in controlling gene expression during normal cellular proliferation and cancer development.

Animals↗

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↗

PubMed1998

Genesis versus epigenesis: the odd jobs of the Polycomb group of genes.

Cells need the products of the Polycomb Group of genes (PcG) to keep, through development, the memory of their genetic determination. The pleiotropic mutant phenotypes of PcG genes strikingly resemble morphological traits, considered as taxonomic characters with phylogenetic meaning, used in Dipteran classification. I argue that spatial modulation of the multimeric complexes formed by PcG products has played a role or escorted the genesis of species.

Animals↗

PubMed2006

Differential expression of polycomb repression complex 1 (PRC1) members in the developing mouse brain reveals multiple complexes.

Polycomb group (PcG) genes are regulators of body segmentation and cell growth, therefore being important players during development. PcG proteins form large complexes (PRC) that fulfil mostly repressive regulative functions on homeotic gene expression. Although expression of PcG genes in the brain has been noticed, the involvement of PcG genes in the processes of brain development is not understood. In this study, we analysed the expression patterns of PRC1 complex members to reveal PcG proteins that might be relevant for mouse brain development. Using in situ hybridisation, we show PRC1 activity in proliferative progenitor cells during neurogenesis, but also in maturated neuronal structures. PRC1 complex compositions vary in a spatial and temporal controlled manner during mouse brain development, providing cellular tools to act in different developmental contexts of cell proliferation, cell fate determination, and differentiation.

Animals↗

PubMed2004

Distinct expression patterns of polycomb oncoproteins and their binding partners during the germinal center reaction.

Polycomb group (PcG) genes encode two chromatin-binding protein complexes, the PRC1 and the PRC2 PcG complexes, which are essential for the maintenance of cell identity and play a role in oncogenesis. PcG complexes were recently identified as novel regulators of hematopoiesis, and appear to be expressed in a non-overlapping pattern in resting and mature follicular B cells. Using highly specific antisera in combination with immunohistochemistry and triple immunofluorescence, we investigated the expression pattern of nine human PcG genes in germinal center (GC) B cells and highly purified germinal center B cell subpopulations. PcG proteins were detected in characteristic binding patterns that were not necessarily related to mutually exclusive expression of the two PcG complexes. We conclude that the two PcG complexes are expressed throughout GC development, and that the fine composition of each complex is determined by the differentiation status of the cell. In addition, a subset of dividing cells with a centrocyte CD marker profile was identified that co-expresses core components of the PRC1 and PRC2 complex. We propose that these cells reflect a transitional stage between resting and dividing follicular B lymphocytes, and that they possibly represent the healthy precursors of nodal large B cell lymphomas.

B-Lymphocytes↗

PubMed2006

The gene for polycomb group protein enhancer of zeste homolog 2 (EZH2) is amplified in late-stage prostate cancer.

Overexpression of the polycomb group protein enhancer of zeste homologue 2 (EZH2) has been found in several malignancies, including prostate cancer, with an aggressive phenotype. Amplification of the gene has previously been demonstrated in several malignancies, but not in prostate cancer. Our goal was to evaluate the gene copy number and expression alterations of EZH2 in prostate cancer. The copy number of EZH2 in cell lines (LNCaP, DU145, PC-3, 22Rv1), xenografts (n = 10), and clinical tumors (n = 191) was studied with fluorescence in situ hybridization. All cell lines had a gain of EZH2. Eight of the ten xenografts showed an increased copy number of the gene, including one case of high-level amplification (>or=5 copies of the gene and EZH2/centromere ratio >or=2). 34/125 (27%) of untreated prostate carcinomas showed increased copy number, but only one case of low-level amplification (>or=5 copies of the gene and EZH2/centromere ratio <2), whereas half (25/46) of the hormone-refractory carcinomas showed increased copy number, including seven cases of low-level amplification and three cases of high-level amplification (P < 0.0001). Expression of EZH2 was significantly (P = 0.0009) higher in hormone-refractory prostate cancer compared with that in benign prostatic hyperplasia or untreated cancer, according to quantitative real-time RT-PCR assay. Also, the expression of EZH2 protein was found to be higher in hormone-refractory tumors than in hormone-naïve tumors by immunohistochemistry. The EZH2 gene amplification was significantly (P < 0.05) associated with increased EZH2 protein expression. The data show that amplification of the EZH2 gene is rare in early prostate cancer, whereas a fraction of late-stage tumors contains the gene amplification leading to the overexpression of the gene, thus indicating the importance of EZH2 in the progression of prostate cancer.

Cell Line, Tumor↗

PubMed1991

Direct interaction of the Polycomb protein with Antennapedia regulatory sequences in polytene chromosomes of Drosophila melanogaster.

The Polycomb (Pc) gene is responsible for the elaboration and maintenance of the expression pattern of the homeotic genes during development of Drosophila. In mutant Pc- embryos, homeotic transcripts are ectopically expressed, leading to abdominal transformations in all segments. From this it was suggested that PC+ acts as a repressor of homeotic gene transcription. We have mapped the cis-acting control sequences of the homeotic Antennapedia (Antp) gene regulated by Pc. Using Antp P1 and P2 promoter fragments linked to the E. coli lacZ reporter gene we show different expression patterns of beta-galactosidase (beta-gal) in transformed Pc+ and Pc- embryos. In addition we are able to visualize by immunocytochemical techniques on polytene chromosomes the direct binding of the Pc protein to the transposed cis-regulatory promoter fragments. However, short Antp P1 promoter constructs which are--due to position effects--ectopically activated in salivary glands, do not reveal a Pc binding signal.

Animals↗

PubMed1994

A Polycomb response element in the Ubx gene that determines an epigenetically inherited state of repression.

Segmentation genes provide the signals for the activation and regulation of homeotic genes in Drosophila but cannot maintain the resulting pattern of expression because their activity ceases halfway through embryogenesis. Maintenance of the pattern is due to the Polycomb group of genes (Pc-G) and the trithorax group of genes (trx-G), responsible for the persistence of the active or repressed state of homeotic genes. We have identified a regulatory element in the Ubx gene that responds to Pc-G and trx-G genes. Transposons carrying this element create new binding sites for Pc-G products in the polytene chromosomes. This Pc-G maintenance element (PRE), establishes a repressive complex that keeps enhancers repressed in cells in which they were originally repressed and maintains this state through many cell divisions. The trx-G products stimulate the expression of enhancers in cells in which they were originally active. This mechanism is responsible for the correct regulation of imaginal disc enhancers, which lack themselves antero-posterior positional information. The PRE also causes severe variegation of the mini-white gene present in the transposon, a phenomenon very similar to heterochromatic position-effect variegation. The significance of this mechanism for homeotic gene regulation is discussed.

Animals↗

PubMed1995

mel-18, a Polycomb group-related mammalian gene, encodes a transcriptional negative regulator with tumor suppressive activity.

The mammalian mel-18/bmi-1 gene products share an amino acid sequence and a secondary structure, including a RING-finger motif, with the Drosophila Polycomb group (PcG) gene products Psc and Su(z)2, implying that they represent a gene family with related functions. As Drosophila PcG gene products are thought to function as transcriptional repressors by modifying chromatin structure, Mel-18/Bmi-1 might be expected to have similar activities. Here we have analyzed the function of mel-18 and found that Mel-18 acts as a transcriptional repressor via its target DNA sequence, 5'-GACTNGACT-3'. Interestingly, this binding sequence is found within regulatory or non-coding regions of various genes, including the c-myc, bcl-2 and Hox genes, suggesting diverse functions of mel-18 as the mammalian homolog of the PcG gene. We also demonstrate that mel-18 has tumor suppressor activity, in contrast to bmi-1, which has been defined as a proto-oncogene.

3T3 Cells↗