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Results for “Polycomb Repressive Complex 1”

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PubMed1999

The P-Ph protein-mediated repression of yellow expression depends on different cis- and trans-factors in Drosophila melanogaster.

The ph(P1) allele of Drosophila melanogaster encodes a chimeric P-Ph protein that contains the DNA-binding domain of the P-element transposase and the Ph protein lacking 12 amino-terminal amino acids. It has been shown that the P-Ph protein is responsible for the formation of a repressive complex on P elements inserted at the yellow locus. Here we demonstrate that an enhancer element can suppress the P-Ph-mediated inhibition of yellow transcription. However, an increase of P-element copy number at the yellow locus overcomes the enhancer effect. The mobilization of P-element transposition induced the appearance with a high frequency of Su(y) mutations that partially or completely suppressed the inhibitory effect of ph(P1) on yellow expression. The Su(y) mutations were localized at different sites on chromosomes. One strong Su(y) mutation, sn(eP1), was found to be induced by a 1.2-kb P-element insertion into the transcribed noncoding region of the singed locus. The Su(y) mutations resulted in a high level of transcription of the 1.2-kb P element that contained the sequences encoding one DNA-binding and two protein-protein interaction domains of the transposase. The effect of Su(y) mutations can be explained by the competition between the truncated transposase encoded by a 1.2-kb P element and the P-Ph protein for binding sites on P-element insertions.

Animals↗
PubMed1999

The mcp element from the Drosophila melanogaster bithorax complex mediates long-distance regulatory interactions.

In the studies reported here, we have examined the properties of the Mcp element from the Drosophila melanogaster bithorax complex (BX-C). We have found that sequences from the Mcp region of BX-C have properties characteristic of Polycomb response elements (PREs), and that they silence adjacent reporters by a mechanism that requires trans-interactions between two copies of the transgene. However, Mcp trans-regulatory interactions have several novel features. In contrast to classical transvection, homolog pairing does not seem to be required. Thus, trans-regulatory interactions can be observed not only between Mcp transgenes inserted at the same site, but also between Mcp transgenes inserted at distant sites on the same chromosomal arm, or even on different arms. Trans-regulation can even be observed between transgenes inserted on different chromosomes. A small 800-bp Mcp sequence is sufficient to mediate these long-distance trans-regulatory interactions. This small fragment has little silencing activity on its own and must be combined with other Polycomb-Group-responsive elements to function as a "pairing-sensitive" silencer. Finally, this pairing element can also mediate long-distance interactions between enhancers and promoters, activating mini-white expression.

Animals↗
PubMed2000

A screen for new trithorax group genes identified little imaginal discs, the Drosophila melanogaster homologue of human retinoblastoma binding protein 2.

The proteins encoded by two groups of conserved genes, the Polycomb and trithorax groups, have been proposed to maintain, at the level of chromatin structure, the expression pattern of homeotic genes during Drosophila development. To identify new members of the trithorax group, we screened a collection of deficiencies for intergenic noncomplementation with a mutation in ash1, a trithorax group gene. Five of the noncomplementing deletions uncover genes previously classified as members of the Polycomb group. This evidence suggests that there are actually three groups of genes that maintain the expression pattern of homeotic genes during Drosophila development. The products of the third group appear to be required to maintain chromatin in both transcriptionally inactive and active states. Six of the noncomplementing deficiencies uncover previously unidentified trithorax group genes. One of these deficiencies removes 25D2-3 to 26B2-5. Within this region, there are two, allelic, lethal P-insertion mutations that identify one of these new trithorax group genes. The gene has been called little imaginal discs based on the phenotype of mutant larvae. The protein encoded by the little imaginal discs gene is the Drosophila homologue of human retinoblastoma binding protein 2.

Animals↗
PubMed2003

Telomeric associated sequences of Drosophila recruit polycomb-group proteins in vivo and can induce pairing-sensitive repression.

In Drosophila, relocation of a euchromatic gene near centromeric or telomeric heterochromatin often leads to its mosaic silencing. Nevertheless, modifiers of centromeric silencing do not affect telomeric silencing, suggesting that each location requires specific factors. Previous studies suggest that a subset of Polycomb-group (PcG) proteins could be responsible for telomeric silencing. Here, we present the effect on telomeric silencing of 50 mutant alleles of the PcG genes and of their counteracting trithorax-group genes. Several combinations of two mutated PcG genes impair telomeric silencing synergistically, revealing that some of these genes are required for telomeric silencing. In situ hybridization and immunostaining experiments on polytene chromosomes revealed a strict correlation between the presence of PcG proteins and that of heterochromatic telomeric associated sequences (TASs), suggesting that TASs and PcG complexes could be associated at telomeres. Furthermore, lines harboring a transgene containing an X-linked TAS subunit and the mini-white reporter gene can exhibit pairing-sensitive repression of the white gene in an orientation-dependent manner. Finally, an additional binding site for PcG proteins was detected at the insertion site of this type of transgene. Taken together, these results demonstrate that PcG proteins bind TASs in vivo and may be major players in Drosophila telomeric position effect (TPE).

Animals↗
PubMed2025

Analysis of a BCOR internal tandem duplication in mouse embryonic stem cell to neuronal precursor differentiation.

BCOR (BCL-6 corepressor) is a component of variant Polycomb Repressive Complex 1.1 (vPRC1.1), one of several vPRC1 complexes that catalyze histone H2A ubiquitination thought to play an important role in PRC2 binding and the deposition of H3K27me3 to silence genes. The PCGF Ub-like fold discriminator (PUFD) domain at the C-terminus of BCOR forms a heterodimer with PCGF1, serving as a critical interface for its polycomb-dependent functions. Internal tandem duplication (ITD) mutations in BCOR, causing in-frame duplications of 20 to 40 amino acids in the PUFD domain, are observed in heterogeneous tumors including sarcomas (kidney, bone, and endometrium) and neuroepithelial tumors in the brain. To dissect the molecular mechanisms underlying aberrant function of BCOR-ITD mutants, we employed mouse embryonic stem (mES) cells expressing either transgenic or endogenous BCOR-ITD. Our results indicate that the BCOR-ITD mutation does not disrupt the BCOR-PCGF1 interaction, instead maintaining the integrity of the vPRC1.1 complex. While displaying subtle changes in imprinted gene expression during differentiation toward a neural lineage, BCOR-ITD mutants also had no growth phenotype in culture. Furthermore, we found that CD24+ cells were enriched, as expected, during neural progenitor differentiation in both wildtype and mutant cells. However, sensitization of BCOR-ITD mES cells with EZH2 inhibitor during differentiation resulted in an unexpected enrichment of a CD24+CD26+ subpopulation, indicating aberrant cell fate that was also prevalent in a BCOR truncation mutant. Together, our results suggest that BCOR-ITD may largely retain wildtype function, but with increased susceptibility to synergistic stress on the Polycomb pathway.

Animals↗
PubMed1993

Characterization and chromosomal localization of the human proto-oncogene BMI-1.

The proto-oncogene bmi-1 is frequently activated by Moloney murine leukemia proviral insertions in E mu-myc transgenic mice1,2. Using a mouse bmi-1 cDNA probe a transcript of 3.3 kb was detected on Northern blots of human Burkitt's lymphoma cell lines. We have isolated and sequenced cDNA clones from a human erythroleukemia cell line (K562) derived cDNA library, using different mouse bmi-1 cDNA fragments as a probe. Analysis of genomic BMI-1 sequences reveals a gene structure which is very similar to that of the mouse, consisting of at least 10 exons. The human cDNA is 3203 bp in length and shows 86% identity to the mouse nucleotide sequence. The open reading frame encodes a protein of 326 amino acids which shares 98% identity to the amino acid sequence of mouse bmi-1 protein. In vitro translation experiments show that human cDNA derived RNA translates into a protein with a mobility of 44-46 kD on SDS polyacrylamide gels. Fluorescence in situ hybridization (FISH) on metaphase chromosome spreads located the human BMI-1 gene to the short arm of chromosome 10 (10p13), a region known to be involved in translocations in various leukemias.

Amino Acid Sequence↗
PubMed1995

The chromo superfamily: new members, duplication of the chromo domain and possible role in delivering transcription regulators to chromatin.

Using computer methods for detecting conserved amino acid sequence motifs, we show that the chromatin organization modifier (chromo) domain that has been previously identified in several proteins involved in transcription down-regulation is present in a much larger group of (putative) chromatin-binding proteins, some of which are positive rather than negative regulators of transcription. The most interesting new members of the chromo superfamily are Drosophila male-specific lethal (MSL-3) protein involved in the X chromosome gene dosage compensation in the males and human retinoblastoma-binding protein RBP-1. We show that the chromo domain is duplicated in several chromatin-binding proteins and use this observation to interpret recent results on chromatin binding obtained with chimeric chromo domain-containing proteins. We hypothesize that the chromo domain may be a vehicle that delivers both positive and negative transcription regulators to the sites of their action on chromatin.

Amino Acid Sequence↗
PubMed2003

GAGA facilitates binding of Pleiohomeotic to a chromatinized Polycomb response element.

Polycomb response elements (PREs) are chromosomal elements, typically comprising thousands of base pairs of poorly defined sequences that confer the maintenance of gene expression patterns by Polycomb group (PcG) repressors and trithorax group (trxG) activators. Genetic studies have indicated a synergistic requirement for the trxG protein GAGA and the PcG protein Pleiohomeotic (PHO) in silencing at several PREs. However, the molecular basis of this cooperation remains unknown. Here, using DNaseI footprinting analysis, we provide a high-resolution map of sites for the sequence- specific DNA-binding PcG protein PHO, trxG proteins GAGA and Zeste and the gap protein Hunchback (HB) on the 1.6 kb Ultrabithorax (Ubx) PRE. Although these binding elements are present throughout the PRE, they display clear patterns of clustering, suggestive of functional collaboration at the level of PRE binding. We found that while GAGA could efficiently bind to a chromatinized PRE, PHO alone was incapable of binding to chromatin. However, PHO binding to chromatin, but not naked DNA, was strongly facilitated by GAGA, indicating interdependence between GAGA and PHO already at the level of PRE binding. These results provide a biochemical explanation for the in vivo cooperation between GAGA and PHO and suggest that PRE function involves the integrated activities of genetically antagonistic trxG and PcG proteins.

Base Sequence↗
PubMed2004

RING1 inhibits transactivation of RBP-J by Notch through interaction with LIM protein KyoT2.

The DNA-binding protein recombination signal binding protein-Jkappa (RBP-J) mediates transcriptional activation of the Notch intracellular domain (NIC). In the absence of transcriptional activators, RBP-J suppresses transcription by recruiting co-suppressors. KyoT2 is a LIM domain protein that inhibits the RBP-J-mediated transcriptional activation. Here we provide evidence that the polycomb group protein RING1 interacts with the LIM domains of KyoT2 in yeast and mammalian cells. The interaction between KyoT2 and RING1 was detected both in vitro and in vivo. By using a co-immunoprecipitation assay, we also showed that, though RING1 and RBP-J did not associate directly, the two molecules could be co-precipitated simultaneously by KyoT2, probably through the LIM domains and the RBP-J-binding motif of KyoT2, respectively. These results suggested the formation of a three-molecule complex consisting of RBP-J, KyoT2 and RING1 in cells. Moreover, we found that overexpression of RING1 together with KyoT2 in cells inhibited transactivation of RBP-J by NIC. Suppression of the NIC- mediated transactivation of RBP-J by RING1 was abrogated by overexpression of KBP1, a molecule that competed with RING1 for binding to LIM domains of KyoT2, suggesting that suppression of RBP-J by RING1 was dependent on its associating with KyoT2. Taken together, our data suggested that there might be at least two ways of the KyoT2-mediated suppression of RBP-J, namely competition for binding sites with transactivators, and recruitment of suppressors such as RING1.

Animals↗
PubMed2005

An Sp1/KLF binding site is important for the activity of a Polycomb group response element from the Drosophila engrailed gene.

Polycomb-group response elements (PREs) are DNA elements through which the Polycomb-group (PcG) of transcriptional repressors act. Many of the PcG proteins are associated with two protein complexes that repress gene expression by modifying chromatin. Both of these protein complexes specifically associate with PREs in vivo, however, it is not known how they are recruited or held at the PRE. PREs are complex elements, made up of binding sites for many proteins. Our laboratory has been working to define all the sequences and DNA binding proteins required for the activity of a 181 bp PRE from the Drosophila engrailed gene. Here we show that one of the sites necessary for PRE activity, Site 2, can be bound by members of the Sp1/KLF family of zinc finger proteins. There are 10 Sp1/KLF family members in Drosophila, and nine of them bind to Site 2. We derive a consensus binding site for the Sp1/KLF Drosophila family members and show that this consensus sequence is present in most of the molecularly characterized PREs. These data suggest that one or more Sp1/KLF family members play a role in PRE function in Drosophila.

Amino Acid Sequence↗
PubMed2006

BMI1 is a target gene of E2F-1 and is strongly expressed in primary neuroblastomas.

The oncogene BMI1 encodes a polycomb group transcription factor that is required for embryonic development and self-renewal of stem cells. Despite these important functions little is known about the regulation of BMI1 expression. A cDNA microarray based search for target genes of E2F-1 in neuroblastoma cells expressing a 4-OHT-regulated E2F-1-ER fusion protein identified many hitherto unknown E2F-1 regulated genes. A total of 10% of these genes, including BMI1, encode proteins that function primarily in the regulation of gene expression. The BMI1 promoter contains a putative E2F binding site that was required for the activation of a BMI1 promoter-dependent reporter construct by E2F-1. Chromatin immunoprecipitation revealed 4-OHT-dependent binding of E2F-1-ER and binding of endogenous E2F-1 to the BMI1 promoter in tumor cells. We have previously shown activation of the oncogene MYCN by E2F. Thus, in neuroblastomas deregulated E2F-1 can activate two oncogenes, MYCN and BMI1 that are known to co-operate in tumor formation. Consistent with a role of Bmi1 in neuroblastoma tumorigenesis we found strong Bmi1 expression in primary neuroblastomas. Our results reveal a novel link between E2F and polycomb transcription factors and suggest a role of Bmi1 in neuroblastomas.

Animals↗
PubMed2006

jPREdictor: a versatile tool for the prediction of cis-regulatory elements.

Gene regulation is the process through which an organism effects spatial and temporal differences in gene expression levels. Knowledge of cis-regulatory elements as key players in gene regulation is indispensable for the understanding of the latter and of the development of organisms. Here we present the tool jPREdictor for the fast and versatile prediction of cis-regulatory elements on a genome-wide scale. The prediction is based on clusters of individual motifs and any combination of these into multi-motifs with selectable minimal and maximal distances. Individual motifs can be of heterogenous classes, such as simple sequence motifs or position-specific scoring matrices. Cluster scores are weighted occurrences of multi-motifs, where the weights are derived from positive and negative training sets. We illustrate the flexibility of the jPREdictor with a new predic-tion of Polycomb/Trithorax Response Elements in Drosophila melanogaster. jPREdictor is available as a graphical user interface for online use and for download at http://bibiserv.techfak.uni-bielefeld.de/jpredictor.

Animals↗
PubMed1996

Structural organization of the rae28 gene, a putative murine homologue of the Drosophila polyhomeotic gene.

A putative murine homologue of the Drosophila polyhomeotic gene, named rae28, has been isolated from a genomic library of 129/SV mouse and its structural organization has been analyzed. rae28 is a single gene of approximately 22 kb long and consists of 15 exons. Its 5'-flanking region lacks typical transcriptional regulatory sequences, such as TATA and CCAAT boxes, but contains GC-rich sequences and seven putative binding sites for a transcription factor, Sp1. One major transcription start point has been determined. The overall exon-intron organization suggested that three different Rae28 mRNAs are generated through alternative splicing. Furthermore, the rae28 gene has been located on the R-positive F3 band of mouse chromosome 6 by the direct R-banding fluorescence in situ hybridization methods.

Animals↗
PubMed2004

Fetal human neural progenitors can be the target for tumor transformation.

The hypothesis that stem cells may seed cancer has emerged from the cancer stem cells concept. However, the experimental systems necessary to provide more direct evidence to support the hypothesis have been lacking. We have used fetal neural progenitor cells (hNPC) transduced with the telomerase hTERT gene to investigate the neoplastic potential of hNPCs. The hTERT-transduced line, hNPCs-G3 lost normal diploid karyotype, showed loss of contact inhibition, anchorage independence, and formed neuroblastoma-like tumours in all of 10 mice. These data suggest that hNPCs have the potential for neoplastic transformation. These data have implications for providing a novel tool to test the feasibility of new anticancer treatment strategies and raise the possibility of a risk for the use of hNPCs in cell transplantation.

Animals↗
PubMed1997

Identification of Bmi1-interacting proteins as constituents of a multimeric mammalian polycomb complex.

The Bmi1 gene has been identified as a mouse Polycomb group (Pc-G) gene implicated in the regulation of Hox gene expression. Here we describe the characterization of a Bmi binding protein Mph1, which shares similarity to Drosophila polyhomeotic. Coimmunoprecipitation experiments indicate that Bmi1 and Mph1, as well as the Mel18 and M33 proteins described previously, are constituents of a multimeric protein complex in mouse embryos and human cells. A central domain of Bmi1 interacts with the carboxyl terminus of Mph1, whereas a conserved alpha-helical domain in the Mph1 protein is required for its homodimerization. Transgenic mice overexpressing various mutant Bmi1 proteins demonstrate that the central domain of Bmil is required for the induction of anterior transformations of the axial skeleton. Bmi1, M33, and Mph1 show an overlapping speckled distribution in interphase nuclei. These data provide molecular evidence for the existence of a mammalian Polycomb complex.

Amino Acid Sequence↗
PubMed2003

Regulation of Polycomb group complexes by the sequence-specific DNA binding proteins Zeste and GAGA.

Repression and activation of the expression of homeotic genes are maintained by proteins encoded by the Polycomb group (PcG) and trithorax group (trxG) genes. Complexes formed by these proteins are targeted by PcG or trxG response elements (PREs/TREs), which share binding sites for several of the same factors. GAGA factor and Zeste bind specifically to PREs/TREs and have been shown to act as both activators and repressors. We have used purified proteins and complexes reconstituted from recombinant subunits to characterize the effects of GAGA and Zeste proteins on PcG function using a defined in vitro system. Zeste directly associates with the PRC1 core complex (PCC) and enhances the inhibitory activity of this complex on all templates, with a preference for templates with Zeste binding sites. GAGA does not stably associate with PCC, but nucleosomal templates bound by GAGA are more efficiently bound and more efficiently inhibited by PCC. Thus Zeste and GAGA factor use distinct means to increase repression mediated by PRC1.

Animals↗
PubMed2004

Growth retardation and premature aging phenotypes in mice with disruption of the SNF2-like gene, PASG.

Imperfect maintenance of genome integrity has been postulated to be an important cause of aging. Here we provide support for this hypothesis by demonstrating that the disruption of PASG (lsh), a SNF2-like factor that facilitates DNA methylation, causes global hypomethylation, developmental growth retardation and a premature aging phenotype. PASG mutant mice display signs of growth retardation and premature aging, including low birth weight, failure to thrive, graying and loss of hair, reduced skin fat deposition, osteoporosis, kyphosis, cachexia, and premature death. Fibroblasts derived from PASG mutant embryos show a replicative senescence phenotype. Both PASG mutant mice and fibroblasts demonstrate a markedly increased expression of senescence-associated tumor suppressor genes, such as p16(INK4a), that is independent of promoter methylation, but, instead, is associated with down-regulation of bmi-1, a negative regulator of p16(INK4a). These studies show that PASG is essential for properly maintaining DNA methylation and gene expression patterns that are required for normal growth and longevity. PASG mutant mice provide a useful model for the study of aging as well as the mechanisms regulating epigenetic patterning during development and postnatal life.

Aging, Premature↗