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PubMed2005

Maintenance of gene expression patterns.

In development, cells pass on established gene expression patterns to daughter cells over multiple rounds of cell division. The cellular memory of the gene expression state is termed maintenance, and the proteins required for this process are termed maintenance proteins. The best characterized are proteins of the Polycomb and trithorax Groups that are required for silencing and maintenance of activation of target loci, respectively. These proteins act through DNA elements termed maintenance elements. Here, we re-examine the genetics and molecular biology of maintenance proteins. We discuss molecular models for the maintenance of activation and silencing, and the establishment of epigenetic marks, and suggest that maintenance proteins may play a role in propagating the mark through DNA synthesis.

Animals↗

PubMed1991

Phenotypic consequences and genetic interactions of a null mutation in the Drosophila Posterior Sex Combs gene.

The Posterior Sex Combs (Psc) gene of Drosophila is a member of the Polycomb (Pc) group of transregulatory genes. Previous analyses of the function of this gene in Drosophila embryogenesis have been hampered by the lack of a null mutation. We recently isolated a mutation that deletes the 5' end of the Psc gene. This allele appears to be a null mutation, and we have used it to determine the Psc zygotic null phenotype and to look at the interactions of a null allele of Psc with five other Pc group mutations. We find evidence for transformations along both the anterior-posterior and dorsal-ventral axes in embryos of a variety of genotypes that include a null mutation in Psc. The phenotypes of embryos that are doubly mutant for a null allele of Psc and a mutation in a second Pc group gene show dramatic synergistic effects, but in their specifics they are dependent on the identity of the second Pc group gene. This is different from the relatively uniform phenotypes seen among double mutants that contained the allele Psc1, which has both gain and loss of function properties. The differences in the phenotypes of the doubly mutant embryos allow us to eliminate one class of molecular models to explain the dramatic synergism seen with mutations in this group of genes.

Animals↗

PubMed1994

Spreading the silence: epigenetic transcriptional regulation during Drosophila development.

In early Drosophila development a complex cascade of diffusible transcription factors generates an intricate expression pattern of developmental regulators such as the homeotic genes. The mechanism which subsequently maintains the pattern during the rest of development is mainly using epigenetic features for its function. Evidence comes from the analysis of the Polycomb-group (Pc-G), a class of genes which is responsible for maintaining the inactive state of expression. The Pc-G was found to share many parallels to genes involved in heterochromatin formation. Different members of the Pc-G interact in large multiprotein complexes, which apparently can cover and inactivate large chromosomal domains. Specific DNA elements have been identified that are used by the Pc-G proteins to nucleate these specialized domains of silent chromatin. Thus, the Pc-G proteins appear to permanently inactivate genes by generating heterochromatin-like structures which could then be inherited by the daughter cells in an epigenetic manner. Heritable gene silencing is an important but little understood mechanism in pattern formation. Phenomenologically related effects have been observed in many organisms. These range from the transcriptional silencing of the inactive mating type loci in yeast to parental imprinting phenomena and X-chromosome inactivation in mammals. Analysis of these functions in Drosophila provides an excellent model system for studying the molecular basis of such epigenetic mechanisms that use higher order chromatin structures for transcriptional repression.

Animals↗

PubMed2002

The cancer-related protein SSX2 interacts with the human homologue of a Ras-like GTPase interactor, RAB3IP, and a novel nuclear protein, SSX2IP.

The SSX gene family is composed of at least five functional and highly homologous members, SSX1 to SSX5, that are normally expressed in only the testis and thyroid. SSX1, SSX2, or SSX4 may be fused to the SYT gene as a result of the t(X;18) translocation in synovial sarcoma. In addition, the SSX1, SSX2, SSX4, and SSX5 genes were found to be aberrantly expressed in several other malignancies, including melanoma. The SSX proteins are localized in the nucleus and are diffusely distributed. In addition, they may be included in polycomb-group nuclear bodies. Other studies have indicated that the SSX proteins may act as transcriptional repressors. As a first step toward the elucidation of the cellular signaling networks in which the SSX proteins may act, we used the yeast two-hybrid system to identify SSX2-interacting proteins. By doing so, two novel human proteins were detected: RAB3IP, the human homolog of an interactor of the Ras-like GTPase Rab3A; and a novel protein, SSX2IP. RAB3IP did not interact with either SSX1, SSX3, or SSX4 in the yeast two-hybrid system, whereas SSX2IP interacted with SSX3 but not with either SSX1 or SSX4. Further analysis of deletion mutants showed that both RAB3IP and SSX2IP interact with the N-terminal moiety of the SSX2 protein. Immunofluorescence analyses of transfected cells revealed that the RAB3IP protein is normally localized in the cytoplasm. However, coexpression of both RAB3IP and SSX2 led to colocalization of both proteins in the nucleus. Likewise, the SSX2IP protein was found to be colocalizing with SSX2 in the nucleus. By performing glutathione-S-transferase pull-down assays, we found that both RAB3IP and SSX2IP interact directly with SSX2 in vitro. These newly observed protein/protein interactions may have important implications for the mechanisms underlying normal and malignant cellular growth.

Adult↗

PubMed2004

Structural integrity and expression of the L3MBTL gene in normal and malignant hematopoietic cells.

The human L3MBTL gene is located in 20q12, a region that is commonly deleted in myeloproliferative disorders (MPD), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). L3MBTL is highly homologous to the D-lethal(3) malignant brain tumor [D-l(3)mbt] gene, which is a putative tumor-suppressor gene (TSG) identified in Drosophila and which is closely related to the Drosophila sex combs on midleg (SCM) protein, a member of the Polycomb group (PcG) family of transcriptional repressors. To examine whether L3MBTL functions as a "classic" TSG in human hematologic malignancies, we screened a panel of 17 myeloid leukemia cell lines and peripheral blood or bone marrow samples from 29 MDS and 13 MPD patients for mutations in the entire L3MBTL coding sequence, including intron/exon splice junctions. No mutations were identified, although two single nucleotide differences were found (in intron 14 and in exon 15), which were interpreted as polymorphic changes. We used real-time RT-PCR to quantify the level of L3MBTL mRNA in various normal myeloid and lymphoid cell populations. L3MBTL is expressed in normal CD34+ bone marrow cells, and we found that the pattern of L3MBTL expression was similar to that of BMI1, a well-studied PcG gene with oncogenic activity, suggesting that L3MBTL and BMI1 may be co-regulated during hematopoiesis. The expression of L3MBTL mRNA in 30 of 35 cell lines and 13 of 15 AML samples was comparable to the level of L3MBTL expression in the normal cell populations. However, five leukemia cell lines showed no L3MBTL expression, and two of the AML samples showed aberrant L3MBTL expression. These data suggest that L3MBTL is not mutated in MDS or MPD. However, given the known dosage effects of PcG proteins in regulating gene expression, reduced or absent L3MBTL expression may be relevant in some cases of myeloid leukemia.

Antigens, CD34↗

PubMed2007

The (epi)genetics of human synovial sarcoma.

Human synovial sarcomas are aggressive soft tissue tumors with relatively high rates of recurrences and metastases. They display a variable response to common treatment protocols such as radiation and chemotherapy. For the development of novel diagnostic, prognostic, and therapeutic approaches, detailed information on the molecular mechanisms underlying the development of these tumors is of imperative importance. Fusion of the SS18 and (one of the) SSX genes is a molecular hallmark of human synovial sarcomas. The SS18 and SSX genes encode nuclear proteins that exhibit opposite transcription regulatory activities, likely through epigenetic mechanisms. The SS18 protein functions as a transcriptional coactivator and interacts directly with members of the epigenetic chromatin remodeling and modification machineries. In contrast, the SSX proteins function as transcriptional corepressors and are associated with several Polycomb group proteins. Since the domains involved in these apparently opposite transcription regulatory activities are retained in the SS18-SSX fusion proteins, we hypothesize that these fusion proteins function as "activator-repressors" of transcription. The implications of this model for human synovial sarcoma development and future treatment are discussed.

Epigenesis, Genetic↗

PubMed2004

RNA polymerase II 140wimp mutant and mutations in the TFIIH subunit XPB differentially affect homeotic gene expression in Drosophila.

Mutations in the XPB and XPD helicases of the DNA repair/transcription factor TFIIH are involved in several human genetic disorders. An unanswered problem concerning the complexity of the phenotype-genotype relationship is why mutations in individual subunits of TFIIH produce specific phenotypes and not many others. In order to investigate this question we tested whether mutations in the Drosophila XPB homolog, haywire (hay), would modify homeotic derepression phenotypes. In this work, we report that mutations in hay and in the 140-kDa subunit of the RNA polymerase II (RpII140wimp) act as dominant modifiers of the derepression phenotypes of the Sex combs reduced (Scr) and Ultrabithorax (Ubx) genes. The hay mutations only weakly suppress the Scr derepression phenotype caused by the Antp(Scx) mutation but not by Polycomb. In contrast, the RpII140wimp mutation strongly suppresses both Scr derepression phenotypes. In addition, the RpII140wimp also generates phenotypes indicative of loss of Ubx function. On the other hand, all the derepression homeotic phenotypes are sensitive to the generalized reduction of transcription levels when the flies are grown with actinomycin D. We also show that different promoter control regions have differential sensitivity to different hay alleles. All these results support that although TFIIH is a basal transcription factor, mutations in the subunit encoded by hay have specific effects in the transcription of some genes.

Animals↗

PubMed1982

Gene-dose titration analysis in the search of trans-regulatory genes in Drosophila.

We have searched for trans-regulatory genes in two genetic systems in Drosophila, the bithorax complex (BX-C) and the achaete-scute complex (AS-C). Previous genetic evidence suggests that the activation of both BX-C and AS-C, depends on trans-regulatory genes (Polycomb, Pc, in the former and hairy, h, in the latter) acting in a negative type of control. Mutants of these regulatory genes in heterozygous condition have dominant derepression phenotypes in flies with extra doses of the corresponding gene complexes. We have searched for new loci, with similar gene-dose relationships. We have isolated only new alleles (six) of Pc in the BX-C experiment. In the AS-C experiment four h alleles, and 13 alleles of a new locus (extramacrochaetae, emc) have been discovered. Whereas the h locus shows specific interactions upon achaete, the new locus, emc, is specific for the scute part of the AS-C. Statistical analysis suggests that these are the only loci in the genome with those dose-dependent properties in the two systems.

Alleles↗

PubMed1988

Developmental analysis of a hybrid gene composed of parts of the Ubx and abd-A genes of Drosophila.

C1 is a mutation in the bithorax complex (BX-C) of Drosophila resulting from the deletion of parts of the Ubx and abd-A genes. We show that the ;hybrid' gene formed by the fusion of the remaining parts of Ubx and abd-A (5'abd-A/Ubx3') is functional and developmentally active. It specifies parasegment patterns with a mixture of thoracic and abdominal identities. The hybrid gene also has other properties typical of conventional bithorax genes: it can be spatially derepressed in the absence of trans-acting genes like extra Sex combs or Polycomb and in turn represses other homeotics like Sex combs reduced. The comparison of embryos containing exclusively hybrid gene activity with others having no BX-C function indicates that the hybrid gene is active in the body region defined by PS5 to PS14. The expression in PS5 and PS6 suggests that one control region (abx) of Ubx can regulate the transcription of the abd-A promoter.

Journal Article↗

PubMed1990

The molecular genetics of the bithorax complex of Drosophila: cis-regulation in the Abdominal-B domain.

In Drosophila the Abdominal-B (Abd-B) domain of the bithorax complex (BX-C) spans over 100 kb and is responsible for specifying the identities of adult abdominal segments five (A5) to nine (A9), inclusive, and correspondingly, neuromeres 10-14 of the embryonic central nervous system. The domain consists of a region coding for two proteins, ABD-BI (54 kd) and ABD-BII (36 kd) and cis-regulatory regions extending from infra-abdominal-5 (iab-5) to iab-9, inclusive. We have used a monoclonal anti-ABD-B antibody to infer that mutants in iab-8 eliminate the expression of ABD-BI in neuromeres 10-13, inclusive, and that mutants in iab-9 eliminate expression of ABD-BII in neuromere 14. ABD-B expression is also analyzed in homozygotes for (i) loss-of-function mutants involving the iab-5, iab-6 and iab-7 regions, (ii) gain-of-function mutants Miscadastral pigmentation (Mcp) and Superabdominal (Sab), and (iii) a trans-regulator, Polycomb (Pc). ABD-B expression along the antero-posterior axis is colinear with the chromosomal order of the cis-regulatory regions. The behavior of rearrangement-associated iab-6 and iab-7 mutants suggests that the enhancer-like region, iab-5, and possibly also iab-6, may be shared between the abd-A and Abd-B domains. Such sharing is proposed as a factor that tends to keep gene complexes intact during evolution.

Abdomen↗

PubMed1991

Long range repression conferring boundaries of Ultrabithorax expression in the Drosophila embryo.

In an attempt to reconstruct the embryonic expression pattern of the homeotic gene Ultrabithorax (Ubx) by stable integration of fusion constructs, we identified three key control regions called PBX, ABX and BXD. Each of these confers an expression pattern mimicking certain aspects of Ubx expression. The PBX and ABX patterns are limited to the Ubx domain with anterior boundaries at parasegments 6 and 5. In contrast, the BXD pattern extends from head to tail. PBX or ABX expression boundaries are imposed on the BXD pattern, if PBX or ABX is linked to BXD. These boundaries, although not the PBX and ABX expression limits themselves, are dependent on Polycomb function. We conclude that PBX and ABX are recognized by repressors which act across large distances to suppress BXD activity. Stable and heritable Ubx expression boundaries are thus mediated by this process of long range repression.

Animals↗

PubMed1993

Silencers in abdominal-B, a homeotic Drosophila gene.

Homeotic genes determine the developmental fates of cells. Restriction of their expression along the body axis is of prime importance for normal development. We searched for cis-regulatory sequences within Abdominal-B (Abd-B), a homeotic Drosophila gene, by testing genomic Abd-B fragments for their ability to confer beta-galactosidase (beta-gal) expression in transformed embryos. One of the Abd-B fragments, called IAB5, mediates a beta-gal pattern restricted along the body axis to the Abd-B expression domain. Alterations of the IAB5 pattern in gap mutants provide evidence that the protein products of the gap genes hunchback, Krüppel and knirps act as repressors through IAB5. The anterior Abd-B expression limit is apparently determined by Krüppel repression, whereas the knirps repressor may be responsible for the graded Abd-B expression within the Abd-B domain. IAB5 and two other fragments called MCP and FAB show region-specific silencing activity: they suppress at a distance beta-gal expression mediated by a linked heterologous enhancer. Silencing requires hunchback as well as Polycomb function and evidently provides maintenance of Abd-B expression limits throughout embryogenesis. We conclude that transcriptional repression is a key mechanism operating at multiple levels to control Abd-B expression. The striking similarities between the control of Abd-B and of Ultrabithorax, another homeotic Drosophila gene, may point to a universal principle underlying homeotic gene regulation.

Animals↗

PubMed2006

Epigenetic modifications in osteogenic differentiation and transformation.

Almost all tumors are characterized by both architectural and cellular abnormalities in differentiation. Osteoblast development is relatively well understood, making osteosarcoma a good model for understanding how tumorigenesis perturbs normal differentiation. We argue that there are two key transition points in normal cellular differentiation that are the focus of oncogenic events, in both of which epigenetic processes are critical. The first is the transition from an uncommitted pluripotent precursor (mesenchymal stem cell) to the 'transit-amplifying compartment' of the osteoblast lineage. This transition, normally exquisitely regulated in space and time, is abnormal in cancer. The second involves termination of lineage expansion, equally tightly regulated under normal circumstances. In cancer, the mechanisms that mandate eventual cessation of cell division are almost universally disrupted. This model predicts that key differentiation genes in bone, such as RUNX2, act in an oncogenic fashion to initiate entry into a proliferative phase of cell differentiation, and anti-oncogenically into the post-mitotic state, resulting in ambivalent roles in tumorigenesis. Polycomb genes exemplify epigenetic processes in the stem cell compartment and tumorigenesis, and are implicated in skeletal development in vivo. The epigenetic functions of the retinoblastoma protein, which plays a key role in tumorigenesis in bone, is discussed in the context of terminal cell cycle exit.

Animals↗

PubMed1993

Perturbed glial scaffold formation precedes axon tract malformation in Drosophila mutants.

The longitudinal glia (LG), progeny of a single glioblast, form a scaffold that presages the formation of longitudinal tracts in the ventral nerve cord (VNC) of the Drosophila embryo. The LG are used as a substrate during the extension of the first axons of the longitudinal tract. I have examined the differentiation of the LG in six mutations in which the longitudinal tracts were absent, displaced, or interrupted to determine whether the axon tract malformations may be attributable to disruptions in the LG scaffold. Embryos mutant for the gene prospero had no longitudinal tracts, and glial differentiation remained arrested at a preaxonogenic state. Two mutants of the Polycomb group also lacked longitudinal tracts; here the glia failed to form an oriented scaffold, but cytological differentiation of the LG was unperturbed. The longitudinal tracts in embryos mutant for slit fused at the VNC midline and scaffold formation was normal, except that it was medially displaced. Longitudinal tracts had intersegmental interruptions in embryos mutant for hindsight and midline. In hindsight, there were intersegmental gaps in the glial scaffold. In midline, the glial scaffold retracted after initial extension. LG morphogenesis during axonogenesis was abnormal in midline. Commitment to glial identity and glial differentiation also occurred before scaffold formation. In all mutants examined, the early distribution of the glycoprotein neuroglian was perturbed. This was indicative of early alterations in VNC pattern present before LG scaffold formation began. Therefore, some changes in scaffold formation may have reflected changes in the placement and differentiation of other cells of the VNC. In all mutants, alterations in scaffold formation preceded longitudinal axon tract formation.

Animals↗

PubMed2026

Diversified cell origin of Helicobacter pylori eradication-responsive gastric diffuse large B-cell lymphomas.

A significant proportion of gastric diffuse large B-cell lymphoma with mucosa-associated lymphoid tissue [DLBCL(MALT)] and without MALT ('pure' DLBCL) can be resolved by Helicobacter pylori eradication (HPE). Gastric MALT lymphoma is an indolent lymphoma derived from memory B cells in the marginal zone. In the present study, we aimed to explore the origin of large cells in HPE-responsive gastric DLBCLs (complete remission after HPE). We investigated gastric lymphoma biopsies from 31 patients with HPE-responsive DLBCLs [15 'pure' DLBCLs, 16 DLBCL(MALT)s]. We used the Hans algorithm (CD10, BCL-6, and MUM1) to define the origins of germinal center B cell (GCB) and non-GCB. To further ascertain the cellular origin, 11 'pure' DLBCLs were examined using an Agilent whole-human genome microarray. Eleven DLBCLs [eight with 'pure' DLBCL and three with DLBCL(MALT)] were also assessed using Lymph2Cx. Specific GCB markers, including BACH2, AID, and BCL2 rearrangement and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) codon 641 mutations, were evaluated in 31 patients with HPE-responsive gastric DLBCLs. According to the Hans algorithm, 53% (8/15) of gastric 'pure' DLBCLs and 50% (8/16) of DLBCL(MALT)s were of the GCB phenotype. Gene expression assays revealed that five of six patients with 'Hans' GCB had GCB genetic signatures, whereas four of five patients with 'Hans' non-GCB had activated B-cell genetic signatures. The Lymph2Cx assay revealed the GCB subtype in seven of eight patients with 'Hans' GCB. The expression patterns of BACH2 (p = 0.005) and AID (p = 0.038) closely correlated with the 'Hans' GCB phenotype. BCL2 rearrangements and EZH2 codon 641 mutations were detected in 44% (7/16) and 13% (2/16) of patients with 'Hans' GCB, respectively. In another cohort of 29 HPE-unresponsive gastric DLBCLs [19 'pure' DLBCLs and 10 DLBCL(MALT)s], we found a close association between the 'Hans' GCB subtype and the GCB subtype as determined by the Agilent whole-human genome microarray and Lymph2Cx in lymphoma cells of these patients. In conclusion, more than half of HPE-responsive large cell lymphoma cases in the stomach were of GCB origin. © 2026 The Pathological Society of Great Britain and Ireland.

Humans↗

PubMed1994

Directed overexpression of suppressor 2 of zeste and Posterior Sex Combs results in bristle abnormalities in Drosophila melanogaster.

Three dominant second-chromosome rearrangement mutations in Drosophila melanogaster, Aristapedioid1 (Arp), vestigial-Depilate (vgD), and vestigial62 (vg62), result in developmental abnormalities of the bristle sense organs on the notum, abdomen, legs, and wing margin. The bristle abnormalities are associated with overexpression of Suppressor 2 of zeste (Su(z)2). We constructed and transformed into flies Hsp70:cDNA constructs for Su(z)2 and the related and neighboring Polycomb group (Pc-G) gene Posterior Sex Combs (Psc). Heat shock-induced overexpression of these two genes (hs-Su(z)2 and hs-Psc) resulted in similar bristle abnormalities that in a developmental stage-specific manner mimicked those seen with the three rearrangement mutations. In addition, hs-Psc overexpression at white prepupae was lethal. The bristle abnormalities are reminiscent of those seen with reduced function of Notch, a neurogenic gene. We found that hs-Su(z)2 overexpression reduced the expression of a lac z enhancer trap in the neurogenic gene neuralized. Previous experiments found that loss of function mutations in Su(z)2 resulted in no bristle abnormalities. Analysis of Psc mitotic clones revealed no essential function of Psc in bristle development. Antibody staining of salivary gland polytene chromosomes showed that after heat shock induction of hs-Psc, Psc protein binds ectopically to hundreds of polytene chromosome loci. These data suggest that the bristle abnormalities seen with overexpression of Su(z)2 and Psc may result from altered expression of genes involved in bristle sense organ development that are not normal regulatory targets of these genes.

Animals↗

PubMed2001

Tantalus, a novel ASX-interacting protein with tissue-specific functions.

The Drosophila trithorax- and Polycomb-group (trxG and PcG) proteins maintain activated and repressed transcriptional states at specific target gene loci. The Additional sex combs (Asx) gene is of particular interest as it appears to function in both protein complexes and yet its effects on target genes are more restricted. A novel protein, Tantalus (TAN), was identified in a yeast two-hybrid screen for ASX-interacting proteins that might confer tissue-specific ASX functions. TAN contains consensus nuclear localization sites and binds DNA in vitro. However, its subcellular localization varies in a tissue-specific fashion. In salivary glands, TAN is predominantly nuclear and associates with 66 euchromatic sites on polytene chromosomes, more than half of which overlap with ASX. These loci do not include the homeotic genes of the ANT and BX complexes bound by other PcG and trxG proteins. Rather, tan mutant defects are restricted to sensory organs. We show that one of these defects, shared by Asx, is genetically enhanced by Asx. Taken together, the data suggest that TAN is a tissue-specific cofactor for ASX, and that its activity may be partially controlled by subcellular trafficking.

Amino Acid Sequence↗

PubMed1998

Chicken chromobox proteins: cDNA cloning of CHCB1, -2, -3 and their relation to W-heterochromatin.

Three clones for chicken chromobox proteins were obtained from liver and ovary cDNA libraries. pCHCB1 and pCHCB2 encode polypeptides showing 96 and 95% identity with mouse M31 and M32, respectively, which are homologues of Drosophila heterochromatin protein 1 (HP1), and pCHCB3 encodes a polypeptide whose sequences of chromobox and C-terminal region show high-level similarities with those of mouse M33, Drosophila polycomb (Pc) protein, and Xenopus Pc homologue. When these cDNAs were expressed in female chicken embryonic fibroblasts (CEFs) as GFP-fused or HA-tagged proteins, all three proteins were found to be localized in nuclei. Among them, CHCB1 associates with brightly stained spots with 4', 6-diamidino-2-phenylindole (DAPI), suggesting its accumulation on heterochromatins. One of those spots was identified as W-heterochromatin. When CHCB1 lacking the N-terminal basic/acidic region or a part of the chromobox region was overexpressed in CEFs, W-heterochromatin became partially or extensively decondensed in the majority of nuclei. Overexpression of CHCB3 lacking a part of the chromobox did not cause decondensation of W-heterochromatin. Specific antisera raised against a part of CHCB1 or CHCB2, produced in Escherichia coli, detected protein species having apparent molecular masses of 25 kDa or 22 plus 23 kDa, respectively, in the subnuclear fraction containing the majority of chromatin from female chicken MSB-1 cells.

Amino Acid Sequence↗