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PubMed2001

The domino gene of Drosophila encodes novel members of the SWI2/SNF2 family of DNA-dependent ATPases, which contribute to the silencing of homeotic genes.

The Drosophila domino gene has been isolated in a screen for mutations that cause hematopoietic disorders. Generation and analysis of loss-of-function domino alleles show that the phenotypes are typical for proliferation gene mutations. Clonal analysis demonstrates that domino is necessary for cell viability and proliferation, as well as for oogenesis. domino encodes two protein isoforms of 3202 and 2498 amino acids, which contain a common N-terminal region but divergent C termini. The common region includes a 500 amino acid DNA-dependent ATPase domain of the SWI2/SNF2 family of proteins, which function via interaction with chromatin. We show that, although domino alleles do not exhibit homeotic phenotypes by themselves, domino mutations enhance Polycomb group mutations and counteract Trithorax group effects. The Domino proteins are present in large complexes in embryo extracts, and one isoform binds to a number of discrete sites on larval polytene chromosomes. Altogether, the data lead us to propose that domino acts as a repressor by interfering with chromatin structure. This activity is likely to be performed as a subunit of a chromatin-remodeling complex.

Adenosine Triphosphatases↗

PubMed2004

Immortalization of cementoblast progenitor cells with Bmi-1 and TERT.

UNLABELLED: A cementoblast progenitor cell line designated BCPb8 was successfully isolated from dental follicle cells immortalized with Bmi-1 and hTERT. BCPb8 showed the potential to differentiate into cementoblasts on implantation into immunodeficient mice. BCPb8 was confirmed to be the first established cementoblast progenitor cell line and will provide a useful model for investigating cementogenesis. INTRODUCTION: The dental follicle is the mesenchymal tissue surrounding the developing tooth germ. During tooth root development, progenitor cells present in the dental follicle are believed to play a central role in the formation of periodontal components (cementum, periodontal ligament, and alveolar bone). However, little more is known about the biology of these progenitors. Previously, we observed that cultured bovine dental follicle cells (BDFCs) contained putative cementoblast progenitors. To further analyze the biology of these cells, we attempted to isolate cementoblast progenitors from immortalized BDFC through expression of the polycomb group protein, Bmi-1, and human telomerase reverse transcriptase (hTERT). MATERIALS AND METHODS: BDFCs were transduced with replication-deficient retroviruses carrying human Bmi-1(LXSN-Bmi-1), and hTERT (LXSH-hTERT) for immortalization. Single cell clones were established from immortalized BDFC, and differentiation into cementoblasts was assessed by implantation into immunodeficient mice. RESULTS AND CONCLUSION: BDFCs expressing Bmi-1 and hTERT showed an extended life span-90 population doublings more than normal BDFCs-and still contained cells with the potential to differentiate into cementoblasts on implantation into immunodeficient mice. From these cells, we established a clonal cell line, designated BCPb8, which formed cementum-like tissue that was reactive to the anti-cementum-specific monoclonal antibody 3G9 and expressed mRNA for bone sialoprotein, osteocalcin, osteopontin, and type I collagen on implantation. Thus, by using Bmi-1 and hTERT, we succeeded in immortalizing cementoblast progenitor cells from BDFC without affecting differentiation potential. The BCPb8 cell line is the first immortalized clonal cell line of cementoblast progenitors and could be a useful tool not only to study cementogenesis but also to develop regeneration therapy for patients with periodontitis.

Animals↗

PubMed2005

Bmi1 loss produces an increase in astroglial cells and a decrease in neural stem cell population and proliferation.

The polycomb transcriptional repressor Bmi1 promotes cell cycle progression, controls cell senescence, and is implicated in brain development. Loss of Bmi1 leads to a decreased brain size and causes progressive ataxia and epilepsy. Recently, Bmi1 was shown to control neural stem cell (NSC) renewal. However, the effect of Bmi1 loss on neural cell fate in vivo and the question whether the action of Bmi1 was intrinsic to the NSCs remained to be investigated. Here, we show that Bmi1 is expressed in the germinal zone in vivo and in NSCs as well as in progenitors proliferating in vitro, but not in differentiated cells. Loss of Bmi1 led to a decrease in proliferation in zones known to contain progenitors: the newborn cortex and the newborn and adult subventricular zone. This decrease was accentuated in vitro, where we observed a drastic reduction in NSC proliferation and renewal because of NSC-intrinsic effects of Bmi1 as shown by the means of RNA interference. Bmi1(-/-) mice also presented more astrocytes at birth, and a generalized gliosis at postnatal day 30. At both stages, colocalization of bromodeoxyuridine and GFAP demonstrated that Bmi1 loss did not prevent astrocyte precursor proliferation. Supporting these observations, Bmi1(-/-) neurospheres generate preferentially astrocytes probably attributable to a different responsiveness to environmental factors. Bmi1 is therefore necessary for NSC renewal in a cell-intrinsic mode, whereas the altered cell pattern of the Bmi1(-/-) brain shows that in vivo astrocyte precursors can proliferate in the absence of Bmi1.

Animals↗

PubMed2004

Characterization of the grappa gene, the Drosophila histone H3 lysine 79 methyltransferase.

We have identified a novel gene named grappa (gpp) that is the Drosophila ortholog of the Saccharomyces cerevisiae gene Dot1, a histone methyltransferase that modifies the lysine (K)79 residue of histone H3. gpp is an essential gene identified in a genetic screen for dominant suppressors of pairing-dependent silencing, a Polycomb-group (Pc-G)-mediated silencing mechanism necessary for the maintenance phase of Bithorax complex (BX-C) expression. Surprisingly, gpp mutants not only exhibit Pc-G phenotypes, but also display phenotypes characteristic of trithorax-group mutants. Mutations in gpp also disrupt telomeric silencing but do not affect centric heterochromatin. These apparent contradictory phenotypes may result from loss of gpp activity in mutants at sites of both active and inactive chromatin domains. Unlike the early histone H3 K4 and K9 methylation patterns, the appearance of methylated K79 during embryogenesis coincides with the maintenance phase of BX-C expression, suggesting that there is a unique role for this chromatin modification in development.

Animals↗

PubMed2006

jing is required for wing development and to establish the proximo-distal axis of the leg in Drosophila melanogaster.

The establishment of the proximo-distal (PD) axis in the legs of Drosophila melanogaster requires the expression of a nested set of transcription factors that are activated in discreet domains by secreted signaling molecules. The precise regulation of these transcription factor domains is critical for generating the stereotyped morphological characteristics that exist along the PD axis, such as the positioning of specific bristle types and leg joints. Here we provide evidence that the Zn-finger protein encoded by the gene jing is critical for PD axis formation in the Drosophila legs. Our data suggest that jing represses transcription and that it is necessary to keep the proximal gene homothorax (hth) repressed in the medial domain of the PD axis. We further show that jing is also required for alula and vein development in the adult wing. In the wing, Jing is required to repress another proximal gene, teashirt (tsh), in a small domain that will give rise to the alula. Interestingly, we also demonstrate that two other genes affecting alula development, Alula and elbow, also exhibit tsh derepression in the same region of the wing disc as jing- clones. Finally, we show that jing genetically interacts with several members of the Polycomb (Pc) group of genes during development. Together, our data suggest that jing encodes a transcriptional repressor that may participate in a subset of Pc-dependent activities during Drosophila appendage development.

Animals↗

PubMed2006

Decreased expression of Bmi1 is closely associated with cellular senescence in small bile ducts in primary biliary cirrhosis.

Cellular senescence of biliary epithelial cells with p16INK4a and p21WAF1/Cip expression in damaged small bile ducts may be critical for progressive bile duct loss in primary biliary cirrhosis. We investigated the involvement of bmi1, a polycomb group gene repressing p16INK4a expression, in the pathogenesis of biliary cellular senescence. Bmi1 expression was examined immunohistochemically in livers taken from the patients with primary biliary cirrhosis (n=18) and other diseased (n=19) and normal livers (n=16). We examined the effect of oxidative stress and a short interference RNA (siRNA) targeting bmi1 on cellular senescence in cultured mouse biliary epithelial cells. Bmi1 was widely expressed in the nuclei of biliary epithelial cells in the control livers. In contrast, bmi1 expression was significantly decreased in damaged small bile ducts in 43% of livers with primary biliary cirrhosis of stage 1/2, coordinating with the increased p16INK4a expression. In cultured biliary epithelial cells, oxidative stress by H2O2 treatment significantly decreased bmi1 expression, followed by increased P16INK4a expression. A knockdown of bmi1 induced increased p16INK4a expression, decreased cell proliferation, and increased cellular senescence. In conclusion, the decreased bmi1 expression caused by oxidative stress may be involved in the pathogenesis of cellular senescence of biliary epithelial cells in primary biliary cirrhosis.

Animals↗

PubMed2000

Structure and chromosomal localization of the RAE28/HPH1 gene, a human homologue of the polyhomeotic gene.

The Polycomb group of (Pc-G) genes and trithorax group of genes are known to play a crucial role in the maintenance of the transcriptional repression state of Hox genes, probably through modification of the chromatin configuration. The rae28/mph1 gene is a mammalian homologue of the Drosophila polyhomeotic gene, which belongs to the Pc-G genes. As reported previously, we established mice deficient in the rae28/mph1 gene and showed that these homozygous animals displayed the developmental defects compatible with a human congenital disorder, CATCH22 syndrome. In this study we analyzed the structural organization of the human counterpart of the rae28/mph1 gene (RAE28/HPH1) and its processed pseudogene (psiPH), which are located on, respectively, human chromosome 12p13 and 12q13. The HPH1 gene consists of 15 exons spanning approximately 26 kb and its structural organization is well conserved between mouse and human. These genetic information of the RAE28/HPH1 gene may provide an important clue for further examination of its involvement in human congenital disorders related to CATCH22 syndrome.

Animals↗

PubMed2006

Cellular senescence, epigenetic switches and c-Myc.

In response to hyperproliferative signaling elicited by transforming oncogenes some normal human cells can enter replicative senescence as a tumor defense mechanism. We recently found that human fibroblasts or endothelial cells with genetically-engineered reduction of proto-oncogene c-Myc expression switched with an increased frequency to a senescent state by a telomere-independent mechanism involving the polycomb group repressor Bmi-1 and the cyclin-dependent kinase inhibitor p16(INK4a). The same regulatory circuit was triggered upon exposure to mild oxidative stress. These findings point to the existence of a mechanism for monitoring hypoproliferative signaling, whose function may be to limit the proliferation and accretion of physiologically compromised cells. This mechanism may be another example of antagonistic pleiotropy leading to organismal aging.

Cell Cycle↗

PubMed2001

BMI-1 gene amplification and overexpression in hematological malignancies occur mainly in mantle cell lymphomas.

The BMI-1 gene is a putative oncogene belonging to the Polycomb group family that cooperates with c-myc in the generation of mouse lymphomas and seems to participate in cell cycle regulation and senescence by acting as a transcriptional repressor of the INK4a/ARF locus. The BMI-1 gene has been located on chromosome 10p13, a region involved in chromosomal translocations in infant leukemias, and amplified in occasional non-Hodgkin's lymphomas (NHLs) and solid tumors. To determine the possible alterations of this gene in human malignancies, we have examined 160 lymphoproliferative disorders, 13 myeloid leukemias, and 89 carcinomas by Southern blot analysis and detected BMI-1 gene amplification (3- to 7-fold) in 4 of 36 (11%) mantle cell lymphomas (MCLs) with no alterations in the INK4a/ARF locus. BMI-1 and p16INK4a mRNA and protein expression were also studied by real-time quantitative reverse transcription-PCR and Western blot, respectively, in a subset of NHLs. BMI-1 expression was significantly higher in chronic lymphocytic leukemia and MCL than in follicular lymphoma and large B cell lymphoma. The four tumors with gene amplification showed significantly higher mRNA levels than other MCLs and NHLs with the BMI-1 gene in germline configuration. Five additional MCLs also showed very high mRNA levels without gene amplification. A good correlation between BMI-1 mRNA levels and protein expression was observed in all types of lymphomas. No relationship was detected between BMI-1 and p16INK4a mRNA levels. These findings suggest that BMI-1 gene alterations in human neoplasms are uncommon, but they may contribute to the pathogenesis in a subset of malignant lymphomas, particularly of mantle cell type.

Cyclin-Dependent Kinase Inhibitor p16↗

PubMed2003

Cancer and epigenesis: a developmental perspective.

Traditionally, molecular geneticists have studied the genome, that is, DNA. This has included its sequencing, with identification of promoters, enhancers, introns, exons, and mutations. During the last 10 to 15 years, it has become clear that this study of "naked" DNA imposed major limitations on our understanding of gene regulation, and that DNA must be studied in conjunction with its protein backbone (chromatin). This new vision has shown that chromatin is a very dynamic molecule, and that changes in DNA methylation, in histones leg, their localization, density, and whether they are acetylated, methylated, phosphorylated and/or ubiquitinated), and in the Polycomb-Trithorax equilibrium are all crucial for the control of gene expression. Furthermore, it was found that like DNA, chromatin-related proteins and DNA methylation are generally passed on unchanged from one cell to its daughters. Thus, gene expression is partly controlled through chromatin modifications that are transmitted from one cell to all its descendants. Such a control is referred to as "epigenetic," as the DNA sequence is not altered. Hence, these epigenetic "marks" can be erased in the early embryo, rendering these cells totipotent. This chapter presents a basic overview of epigenesis in the control of normal embryonal cell differentiation, including imprinting. Similarities between embryonal and cancer cells are highlighted, and the potential impact of chemotherapy aimed at epigenetic mechanisms is reviewed.

Alleles↗

PubMed2004

The indexing potential of histone lysine methylation.

Diverse post-translational modifications of histone N-termini represent an important epigenetic mechanism for the organization of chromatin structure and the regulation of gene activity. Within the last three years, great progress has been made in understanding the functional implications of histone methylation, in particular through the characterization of histone methyltransferases (HMTases) that direct the site-specific methylation of lysine positions in the histone H3 N-terminus. Histone lysine methylation has been linked with pericentric heterochromatin formation, X-inactivation, Polycomb group (Pc-G)-dependent gene repression and epigenetic control of transcription units at euchromatic positions. Together, these regulatory roles have strongly established histone lysine methylation as a central epigenetic modification for the organization of eukaryotic chromatin. However, they also create a paradox: if histone lysine methylation is present at so many chromatin regions, how can it impart epigenetic information? We provide evidence that differences in distinct methylation states (mono- vs. di- vs. trimethylation) and selective combinations of individually methylated lysine positions can indeed index chromatin regions, resulting in epigenetic landmarks for the partitioning of eukaryotic chromatin.

Animals↗

PubMed2006

Temporal and spatial expression of homeotic genes is important for segment-specific neuroblast 6-4 lineage formation in Drosophila.

Different proliferation of neuroblast 6-4 (NB6-4) in the thorax and abdomen produces segmental specific expression pattern of several neuroblast marker genes. NB6-4 is divided to form four medialmost cell body glia (MM-CBG) per segment in thorax and two MM-CBG per segment in abdomen. As homeotic genes determine the identities of embryonic segments along theA/P axis, we investigated if temporal and specific expression of homeotic genes affects MM-CBG patterns in thorax and abdomen. A Ubx loss-of-function mutation was found to hardly affect MM-CBG formation, whereas abd-A and Abd-B caused the transformation of abdominal MM-CBG to their thoracic counterparts. On the other hand, gain-of-function mutants of Ubx, abd-A and Abd-B genes reduced the number of thoracic MM-CBG, indicating that thoracic MM-CBG resembled abdominal MM-CBG. However, mutations in Polycomb group (PcG) genes, which are negative transregulators of homeotic genes, did not cause the thoracic to abdominal MM-CBG pattern transformation although the number of MM-CBG in a few per-cent of embryos were partially reduced or abnormally patterned. Our results indicate that temporal and spa-tial expression of the homeotic genes is important to determine segmental-specificity of NB6-4 daughter cells along the anterior-posterior (A/P) axis.

Abdomen↗

PubMed2006

Anti-cancer vaccine candidates in specific immunotherapy for bladder carcinoma.

We have previously identified numerous tumor-rejection antigens and their epitope peptides having the potential to induce cancer-reactive cytotoxic T lymphocytes (CTLs) in patients with various types of cancer. In the present study, we attempted to determine which antigens and their peptides are useful in specific immunotherapy for bladder carcinoma (BC) patients, especially those with human leukocyte antigen (HLA)-A24+ alleles. The mRNA expression of a panel of cancer-associated antigens was examined regarding four BC cell lines. As a result, three candidate antigens, including SART3, multidrug resistance-associated protein 3 (MRP3), and polycomb group protein enhancer of zeste homolog 2 (EZH2), were expressed in three of four BC cell lines. Thereafter, antigen-derived peptides which we reported to induce cancer-reactive CTLs from HLA-A24+ patients with various types of cancer were examined for their potential to induce CTLs from peripheral-blood mononuclear cells of HLA-A24+ BC patients. Among these antigen-derived six peptides, SART3109-118, MRP31293-1301, and EZH2735-742 peptides efficiently induced peptide-specific and BC cell-reactive CTLs from HLA-A24+ BC patients. The cytotoxicity against BC cells was dependent on peptide-specific CD8+ T cells. IgG reactive to the SART3109-118 peptide was frequently detected in the plasma of BC patients. This information could facilitate the development of effective peptide-based immunotherapy for HLA-A24+ BC patients.

Antigens, Neoplasm↗

PubMed1998

The SAM domain of polyhomeotic, RAE28, and scm mediates specific interactions through conserved residues.

The SAM (sterile alpha motif) domain is a 65- to 70-amino acid sequence found in many diverse proteins whose functions range from signal transduction to transcriptional repression. We show that the SAM domain of the Drosophila Polycomb group protein, polyhomeotic (ph), is capable of binding to itself in vitro. We test a number of near relatives of the ph SAM domain from fruit fly, mouse, and yeast and show that all are capable of self-binding. Heterologous interactions are seen among a subset of SAM domains, including ph, Scm, and RAE28. Several conserved amino acid residues were mutated in the ph SAM domain, and the effects on self-binding and heterologous association were demonstrated. L33, L41, and 162 are shown to be important determinants of the binding interface, while W1 and G50 are likely essential for the structure of the domain.

Amino Acid Sequence↗

PubMed1998

Chromatin complexes as aperiodic microcrystalline arrays that regulate genome organisation and expression.

The current understanding of chromatin-mediated repression in Metazoa stems largely from work on two systems in Drosophila: heterochromatin-induced position-effect variegation and repression of the homeotic genes by the Polycomb-group of genes. A common feature of these two systems is the cooperative assembly of multimeric complexes which can epigenetically silence gene activity. Moreover, both older and more recent work has suggested that these complexes can themselves associate to give rise to larger complexes: The specificity of the association is likely to be determined by complementarity of the structural components of the complexes. Here, we aim to accommodate these, and other, features of chromatin-mediated repression in a single hypothesis, namely the crystallisation hypothesis. This hypothesis views the nucleus as being an environment that favours the formation of chromatin complexes which behave as aperiodic microcrystalline arrays constructed through the cooperative assembly of different types of lattice unit. The lattice units possess regions of structural complementarity that allow interactions between complexes. Aperiodicity confers specificity on the complexes and is a key feature of the model which, we suggest, provides a gene with a "chromosomal address." The chromosomal address allows the side-by-side alignment of homologous chromosomal regions, a properly that may be important in a variety of biologically relevant situations. Aperiodicity is also a feature of the hypothesis that is directly testable.

Animals↗

PubMed2001

Molecular mechanisms underlying human synovial sarcoma development.

Synovial sarcomas are rather common among soft-tissue tumors, occurring at any age but affecting mainly young adults. The vast majority of synovial sarcomas carries a t(X;18)(p11.2;q11.2) chromosomal translocation, in about one-third of the cases as the sole cytogenetic anomaly. Several studies have indicated that the t(X;18) translocation arises exclusively in synovial sarcomas, therefore being an excellent tool to diagnose this malignancy. The breakpoint-associated genes were recently isolated: SYT, from chromosome 18, and SSX1 and SSX2, both from the X chromosome. This discovery enabled the detection of SYT-SSX fusion transcripts by specific reverse transcriptase-polymerase chain reactions. This molecular genetics methodology has now been applied to numerous tumor samples and has led to the finding that, in contrast to tumors carrying SYT-SSX2 fusions, SYT-SSX1-positive tumors more often exhibit a biphasic histology, show a higher proliferation rate, and are associated with a poorer clinical outcome. It has also been shown that the SYT and SSX proteins are localized in the nucleus, where they appear to play a role in transcriptional regulation, SYT as an activator of transcription and the SSX proteins as transcriptional repressors. It was also found that SYT interacts and colocalizes in the nucleus with the BRM protein, a transcriptional coactivator, and that the SSX proteins colocalize in the nucleus with polycomb group proteins, which are transcriptional corepressors. Together, these studies have provided mechanistic clues about how the SYT-SSX fusion proteins may trigger synovial sarcoma development.

Amino Acid Sequence↗

PubMed2006

Eyeing tumorigenesis: Notch signaling and epigenetic silencing of Rb in Drosophila.

Notch signaling plays an essential role in the processes of embryogenesis and cellular differentiation, and it is believed that the oncogenic effects of dysregulated Notch signaling are an anomalous reflection of the normal functions of this cascade. Nonetheless, the cellular events associated with oncogenic Notch signaling have thus far remained elusive. In a recent report, Ferres-Marco et al. described how they used the Drosophila eye as a model system and found that elevated Notch signaling in combination with activation of components of the Polycomb complex of transcriptional repressors led to metastatic growth of tumors through epigenetic silencing of the Rbf gene. Rbf is the Drosophila homologue of the retinoblastoma tumor-suppressor gene (Rb), thus it represents a novel link between Notch signaling, tumor growth and metastasis.

Animals↗

PubMed1994

White gene expression, repressive chromatin domains and homeotic gene regulation in Drosophila.

The use of Drosophila chromosomal rearrangements and transposon constructs involving the white gene reveals the existence of repressive chromatin domains that can spread over considerable genomic distances. One such type of domain is found in heterochromatin and is responsible for classical position-effect variegation. Another type of repressive domain is established, beginning at specific sequences, by complexes of Polycomb Group proteins. Such complexes, which normally regulate the expression of many genes, including the homeotic loci, are responsible for silencing, white gene variegation, pairing-dependent effects and insertional targeting.

Animals↗