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PubMed2000

Delineation of the protein domains responsible for SYT, SSX, and SYT-SSX nuclear localization.

In the vast majority of synovial sarcomas the N-terminal part of the SYT protein is fused to the C-terminal part of an SSX protein, either SSX1 or SSX2. The wild-type proteins, as well as the resultant SYT-SSX1 and SYT-SSX2 fusion proteins, are localized in the nucleus. Recent studies in experimental systems indicated that the SYT protein may function as a transcriptional activator whereas the SSX proteins may act as transcriptional repressors. In the present work we created a series of deletion mutants and found that SYT and SSX depend on N-terminal and highly conserved C-terminal domains for nuclear localization, respectively. Our results also show that the SYT-SSX proteins colocalize with SSX2, a feature that depends on the presence of the C-terminal SSX sequences in the chimeric proteins. Absence of these sequences led to an altered subcellular localization, coinciding with that of SYT. Besides, we found that endogenously expressed SSX proteins colocalize with polycomb-group proteins and condensed chromosomes during mitosis, features that are also conferred by the C-terminus of SSX. Taken together, these results led us to conclude that the SSX moiety, especially the most C-terminal 34 amino acids, of the SYT-SSX fusion proteins is crucial for aberrant spatial targeting and transcriptional control within the nucleus.

Amino Acid Sequence↗

PubMed2006

Epigenetic regulation in Drosophila.

Epigenetic regulation of gene transcription relies on molecular marks like DNA methylation or histone modifications. Here we review recent advances in our understanding of epigenetic regulation in the fruit fly Drosophila melanogaster. In the past, DNA methylation research has primarily utilized mammalian model systems. However, several recent landmark discoveries have been made in other organisms. For example, the interaction between DNA methylation and histone methylation was first described in the filamentous fungus Neurospora crassa. Another example is provided by the interaction between epigenetic modifications and the RNA interference (RNAi) machinery that was first reported in the fission yeast Schizosaccharomyces pombe. Another organism with great experimental power is the fruit fly Drosophila. Epigenetic regulation by chromatin has been extensively analyzed in the fly and several of the key components have been discovered in this organism. In this chapter, we will focus on three aspects that represent the complexity of epigenetic gene regulation. (1) We will discuss the available data about the DNA methylation system, (2) we will illuminate the interaction between DNA methylation and chromatin regulation, and (3) we will provide an overview over the Polycomb system of epigenetic chromatin modifiers that has proved to be an important paradigm for a chromatin system regulating epigenetic programming.

Acetylation↗

PubMed2006

How is epigenetic information on chromatin inherited after DNA replication?

Although most somatic cells have identical genetic information, gene expression profiles are quite distinct in each cell type. The gene expression profiles are considered to be determined mainly by chromatin-encoded epigenetic information that includes histone modifications, histone variants, and factors such as HP1 and polycomb group proteins that organize higher-ordered chromatin structures. To gain insights into how such epigenetic information on chromatin is inherited on daughter DNA strands after DNA replication, we have purified the preassembled form of histone H3 by immunoaffinity purification. The histone H3 complex contains the two histone H3-H4 chaperones CAF1 and ASF1. Surprisingly, the H3 complex also contains a pair of H3-H4 dimers. This observation is striking because histones H3-H4 are known to exist as tetramers in solution. Since histones H3-H4 in the predeposition complex exist as a dimer, this raises the possibility that the H3-H4 dimer in the complex pairs with a parental H3-H4 dimer, assembling the de novo-synthesized and parental H3-H4 dimers in the same nucleosome. Based on these results, we propose a semi-conservative model of nucleosome duplication, which allows for segregation of parental H3-H4 dimers with encoded epigenetic information evenly to daughter DNA strands.

Animals↗

PubMed1985

Polyhomeotic: a gene of Drosophila melanogaster required for correct expression of segmental identity.

A new locus in Drosophila melanogaster that is required for the correct expression of segmental identity has been discovered. The new locus, termed polyhomeotic (ph), is X-linked and maps cytologically to bands 2D2-3. Homozygous ph flies have homeotic transformations similar to those of known dominant gain of function mutants in the Antennapedia and bithorax complexes (ANT-C, BX-C), and in addition show loss of the humerus. ph interacts with three other similar mutations: Polycomb (Pc), Polycomblike (Pcl), and extra sex comb (esc), and acts as a dominant enhancer of Pc. The expression of ph depends on the ANT-C and BX-C dosage. ph has no embryonic phenotype, but temperature shift studies on ph2 show that the ph+ product is required during embryogenesis and larval development. We propose that ph mutants in some way disrupt the normal expression of the ANT-C and BX-C, and, therefore, that ph+ is needed for maintenance of segmental identity.

Animals↗

PubMed2005

The regulation of embryonic patterning and DNA replication by geminin.

Geminin is a multifunctional protein. After DNA replication is initiated during a cell cycle, geminin binds to Cdt1, one of the key DNA replication licensing factors. This highly regulated interaction sequestrates Cdt1, thus preventing DNA rereplication in the same cell cycle. In addition, geminin directly interacts with Six3 and Hox homeodomain proteins during embryogenesis and inhibits their functions. The regulation of Hox function by geminin also involves a transient association with the Hox repressive Polycomb complex. The functions of geminin to obstruct key molecules of both cell proliferation and embryonic development suggest a competitive coordination of these two processes.

Animals↗

PubMed1998

SET domain proteins modulate chromatin domains in eu- and heterochromatin.

The SET domain is a 130-amino acid, evolutionarily conserved sequence motif present in chromosomal proteins that function in modulating gene activities from yeast to mammals. Initially identified as members of the Polycomb- and trithorax-group (Pc-G and trx-G) gene families, which are required to maintain expression boundaries of homeotic selector (HOM-C) genes, SET domain proteins are also involved in position-effect-variegation (PEV), telomeric and centromeric gene silencing, and possibly in determining chromosome architecture. These observations implicate SET domain proteins as multifunctional chromatin regulators with activities in both eu- and heterochromatin--a role consistent with their modular structure, which combines the SET domain with additional sequence motifs of either a cysteine-rich region/zinc-finger type or the chromo domain. Multiple functions for chromatin regulators are not restricted to the SET protein family, since many trx-G (but only very few Pc-G) genes are also modifiers of PEV. Together, these data establish a model in which the modulation of chromatin domains is mechanistically linked with the regulation of key developmental loci (e.g. HOM-C).

Amino Acid Sequence↗

PubMed1999

Differentiation: A central topic in developmental and cell biology.

The concept of "differentiation" encompasses all processes leading to differently specialized cell types, beginning with the progressive divergence of developmental pathways and ending with the successive programming and final elaboration of each particular cell type. Guidance and positional information are provided by external cues, by differentially allotted cytoplasmic determinants such as mRNA for transcription factors, and by cascades of intercellular signals. Eventually cell type specific selector genes, such as the muscle cell determining MyoD/myogenin genes and neural key genes (e. g., achaete scute-C, neurogenin), are switched on which control entire sets of subordinate effector genes. In multiplying cells "cell heredity" based on an epigenetic cellular memory enables transmission of the cell type determining program from parental to daughter cells. This memory can be based on autocatalytic self-activation of cell type specific selector genes and on the enduring action of gene groups such as the Polycomb and thrithorax complexes that code for proteins which bind to DNA sequences called cellular memory modules. These modules confer permanent accessibility (potentiation) or inaccessibility (silencing) upon many different gene loci on the chromosomes.

Animals↗

PubMed1999

Genomic organization of the HSET locus and the possible association of HLA-linked genes with immotile cilia syndrome (ICS).

The kinesin-related protein (HSET) gene belongs to the kinesin superfamily, the members of which are involved in cellular transport processes. The HSET gene product was previously characterized by partial cDNA sequencing. The gene is located on the short arm of human Chromosome 6 (6p21.3), at the centromeric end of the major histocompatibility complex. Here, we report the genomic structure of the complete HSET gene together with its flanking loci. Sequence analysis of the 40 kilobase (kb) cosmid clone containing the HSET gene also revealed the presence of several new genes not related to the kinesin superfamily. These include a 60S ribosomal protein L35A-like pseudogene (rPL35A-like) on the telomeric side and a polycomb-like gene (PHF1), a copper tolerance-like gene (CUTA1) and the 5' part of the synaptic ras-GTPase-activating protein (SynGAP) gene centromeric of HSET. In addition, a complete 60S ribosomal protein L12-like (rPL12L) gene in intron 3 of the HSET gene was identified which appears to have an open reading frame. The possible involvement of the HSET gene and a beta-tubulin gene (TUBB) in the pathogenesis of immotile cilia syndrome (ICS) was studied by screening two unrelated ICS families with microtubular defects and suspected HLA linkage for mutations within the HSET gene and the TUBB gene. Four single base substitutions were detected in the HSET gene, and none in the TUBB gene. On the basis of these data, a role of the HSET and TUBB products in the pathogenesis of ICS in the two families is unlikely.

Amino Acid Sequence↗

PubMed1996

Exclusion of Sox9 as a candidate for the mouse mutant tail-short.

The Sry-related gene Sox9 has been proposed as the gene responsible for the mouse skeletal mutant Tail-short (Ts), on the basis of its expression in skeletogenic mesenchymal condensations in the mouse embryo and its chromosomal location in the region of Ts on distal Chromosome (Chr) 11. We present here detailed mapping of Ts locus relative to the Sox9, using an intersubspecific cross. Among 521 backcross progeny, 16 recombinants were detected between Sox9 and Ts, suggesting a separation of 3.5 +/- 0.01 cM, and excluding Sox9 as a candidate for Ts. A further nine recombinants were detected between Ts and the polycomb-like gene M33, suggesting that these loci are separated by 1.8 +/- 0.011 cM. Six microsatellite markers were co-localized to the Ts locus, providing reagents for positional cloning of Ts.

Animals↗

PubMed1996

Rbt (Rabo torcido), a new mouse skeletal mutation involved in anteroposterior patterning of the axial skeleton, maps close to the Ts (tail-short) locus and distal to the Sox9 locus on chromosome 11.

Rbt (Rabo torcido) is a new semidominant mouse mutant with a variety of skeletal abnormalities. Heterozygous Rbt mutants display homeotic anteroposterior patterning problems along the axial skeleton that resemble Polycomb group and trithorax gene mutations. In addition, the Rbt mutant displays strong similarities to the phenotype observed in Ts (Tail-short), indicating also a homeotically transformed phenotype in these mice. We have mapped the Rbt locus to an interval of approximately 6 cM on mouse Chromosome (Chr) 11 between microsatellite markers D11Mit128 and D11Mit103. The Ts locus was mapped within a shorter interval of approximately 3 cM between D11Mit128 and D11Mit203. This indicates that Rbt and Ts may be allelic mutations. Sox9, the human homolog of which is responsible for the skeletal malformation syndrome campomelic dysplasia, was mapped proximal to D11Mit128. It is, therefore, unlikely that Ts and Rbt are mouse models for this human skeletal disorder.

Animals↗

PubMed2002

Influence of the SuUR gene on intercalary heterochromatin in Drosophila melanogaster polytene chromosomes.

Salivary gland polytene chromosomes of Drosophila melanogaster have a reproducible set of intercalary heterochromatin (IH) sites, characterized by late DNA replication, underreplicated DNA, breaks and frequent ectopic contacts. The SuUR mutation has been shown to suppress underreplication, and wild-type SuUR protein is found at late-replicating IH sites and in pericentric heterochromatin. Here we show that the SuUR gene influences all four IH features. The SuUR mutation leads to earlier completion of DNA replication. Using transgenic strains with two, four or six additional SuUR(+) doses (4-8xSuUR(+)) we show that wild-type SuUR is an enhancer of DNA underreplication, causing many late-replicating sites to become underreplicated. We map the underreplication sites and show that their number increases from 58 in normal strains (2xSuUR(+)) to 161 in 4-8xSuUR(+) strains. In one of these new sites (1AB) DNA polytenization decreases from 100% in the wild type to 51%-85% in the 4xSuUR (+) strain. In the 4xSuUR(+) strain, 60% of the weak points coincide with the localization of Polycomb group (PcG) proteins. At the IH region 89E1-4 (the Bithorax complex), a typical underreplication site, the degree of underreplication increases with four doses of SuUR(+) but the extent of the underreplicated region is the same as in wild type and corresponds to the region containing PcG binding sites. We conclude that the polytene chromosome regions known as IH are binding sites for SuUR protein and in many cases PcG silencing proteins. We propose that these stable silenced regions are late replicated and, in the presence of SuUR protein, become underreplicated.

Animals↗

PubMed2005

Gene activation and deactivation related changes in the three-dimensional structure of chromatin.

Chromatin in the interphase nucleus is dynamic, decondensing where genes are activated and condensing where they are silenced. Local chromatin remodelling to a more open structure during gene activation is followed by changes in nucleosome distribution through the action of the transcriptional machinery. This leads to chromatin expansion and looping out of whole genomic regions. Such chromatin loops can extend beyond the chromosome territory. As several studies point to the location of transcription sites inside chromosome territories as well as at their periphery, extraterritorial loops cannot simply be a mechanism for making transcribed genes accessible to the transcriptional machinery and must occur for other reasons. The level of decondensation within an activated region varies greatly and probably depends on the density of activated genes and the number of engaged RNA polymerases. Genes that are silenced during development form a more closed chromatin structure. Specific histone modifications are correlated with gene activation and silencing, and silenced genes may become associated with heterochromatin protein 1 homologues or with polycomb group complexes. Several levels of chromatin packaging are found in the nucleus relating to the different functions of and performed by active genes; euchromatic and heterochromatic regions and the models explaining higher-order chromatin structure are still disputed.

Animals↗

PubMed2005

DNA methylation and epigenetic inheritance during plant gametogenesis.

In plants, newly acquired epigenetic states of transcriptional gene activity are readily transmitted to the progeny. This is in contrast to mammals, where only rare cases of transgenerational inheritance of new epigenetic traits have been reported (FASEB J 12:949-957, 1998; Nat Genet 23:314-318, 1999; Proc Natl Acad Sci U S A 100:2538-2543, 2003). Epigenetic inheritance in plants seems to rely on cytosine methylation maintained through meiosis and postmeiotic mitoses, giving rise to gametophytes. In particular, maintenance of CpG methylation ((m)CpG) appears to play a central role, guiding the distribution of other epigenetic signals such as histone H3 methylation and non-CpG DNA methylation. The evolutionarily conserved DNA methyltransferase MET1 is responsible for copying (m)CpG patterns through DNA replication in the gametophytic phase. The importance of gametophytic MET1 activity is illustrated by the phenotypes of met1 mutants that are severely compromised in the accuracy of epigenetic inheritance during gametogenesis. This includes elimination of imprinting at paternally silent loci such as FWA or MEDEA (MEA). The importance of DNA methylation in gametophytic imprinting has been reinforced by the discovery of DEMETER (DME), encoding putative DNA glycosylase involved in the removal of (m)C. DME opposes transcriptional silencing associated with imprinting activities of the MEA/FIE polycomb group complex.

CpG Islands↗

PubMed2001

Expression and functional analysis of three isoforms of human heterochromatin-associated protein HP1 in Drosophila.

Heterochromatin-associated protein 1 (HP1) is a nonhistone chromosomal protein associated with pericentromeric heterochromatin in Drosophila. HP1-like proteins have also been found associated with heterochromatin in human cells. The goal of this study was to determine whether proteins of the structurally conserved human HP1 family exhibit conserved heterochromatin targeting and silencing properties in Drosophila. We established transgenic lines of Drosophila melanogaster expressing each of the three human HP1 proteins, HP1Hsalpha, HP1HSbeta, and HP1Hsgamma, under the Hsp70 heat shock promoter. We show that all three isoforms of human HP1 are stably expressed in Drosophila and are associated with heterochromatin in Drosophila chromosomes. Like Drosophila HP1, all three human HP1 proteins are delocalized by an HP1-POLYCOMB chimeric protein, implying that both human HP1 and Drosophila HP1 interact in a common protein complex, and that at least some aspects of heterochromatin structure are highly conserved throughout the evolution of eukaryotes. Ectopic expression of two of the three human HP1 family proteins significantly enhances heterochromatic silencing in Drosophila.

Amino Acid Sequence↗

PubMed1997

The conserved HR domain of the Drosophila suppressor 2 of zeste [Su(z)2] and murine bmi-1 proteins constitutes a locus-specific chromosome binding domain.

The related Drosophila Suppressor 2 of zeste [Su(z)2] and Posterior sex combs (Psc) proteins are both locus-specific chromosome binding proteins. They are found at many of the same polytene chromosome loci as other Polycomb-group proteins. The 1,365 amino acid Su(z)2 protein and the 1,603 amino acid Psc protein share a conserved 200 amino acid domain, the homology region (HR). To identify the protein domain responsible for locus-specific chromosome binding, we made a series of Hsp70:cDNA deletion constructs of the Sz(z)2 gene and transformed these into flies. We found that the HR is necessary and sufficient for Su(z)2 locus-specific polytene chromosome binding. The murine Bmi-1 protein also shares the conserved HR domain. When expressed in flies, the Bmi-1 protein showed a locus-specific chromosome binding pattern similar to that of the Su(z)2 and Psc proteins. These results argue that a locus-specific chromosome binding function resides in the HR domain. Other results show that a second, low affinity, non-specific chromosome binding function is localized outside the HR in the Su(z)2 protein, and that the Su(z)2 protein contains at least two nuclear localization signals.

Animals↗

PubMed2001

Xenopus Polycomblike 2 (XPcl2) controls anterior to posterior patterning of the neural tissue.

A novel gene, Xenopus Polycomblike 2 (XPcl2), which encodes a protein similar to Drosophila Polycomblike was cloned and characterized. Polycomblike belongs to the Polycomb group proteins, which maintain stable expression patterns for the clustered homeotic genes in the Drosophila embryo by forming multimeric complexes on chromatin. XPcl2 shows greater amino acid sequence homology to human and mouse M96 (hPcl2, mPcl2) than Xenopus Pcl1 (XPcl1), mouse Tctex3 (mPcl1) and human PHF1 (hPcl1), indicating that at least two types of Polycomblike genes are conserved between amphibians and mammals. XPcl2 mRNA is present both maternally and zygotically, and the temporal expression profile is distinct from XPcl1, another member of the Polycomblike family in Xenopus. XPcl2 is highly expressed in the anterior-dorsal region of Xenopus following the neurula stage in a manner similar to XPcl1. Overexpression of XPcl2 disturbs the development of the anterior central nervous system, eye and cement gland. In the XPcl2-overexpressing embryo, a hindbrain marker, Krox20, and a spinal cord marker, HoxB9, are expressed more posteriorly, suggesting an alteration in the anterior-posterior patterning of the neural tissue. In addition, XPcl2 represses Zic3- and noggin-induced anterior neural markers, but not neural crest markers in animal cap explants. These results indicate that XPcl2 regulates anterior neural tissue development and the anterior-posterior patterning of the neural tissue.

Amino Acid Sequence↗

PubMed2004

Molecular genetics of the Alhambra (Drosophila AF10) complex locus of Drosophila.

The Alhambra (Alh) gene is the Drosophila homologue of the human AF10 gene. AF10 has been identified as a fusion partner of MLL, a human homologue of the fly gene trithorax, in infant leukemias. The endogenous function of human AF10 is not known, but may be vital to its role in acute leukemia. This prompted us to analyse Alh function. We describe here the genetic organisation of the Alh locus in D. melanogaster. We show that an independent lethal complementation group encoding a muscle protein (Mlp84B) is located within an Alh intron. We have already shown that the leucine zipper (LZ) domain of ALH activates several Polycomb group-responsive elements. We further demonstrate that the LZ domain on its own bears the Alh vital function, since it is necessary and sufficient for rescue of Alh mutant lethality. Finally, we demonstrate that, in contrast to a previous report, Alh does not affect position-effect variegation.

Animals↗

PubMed2001

Advantages of a P-element construct containing MtnA sequences for the identification of patterning and cell determination genes in Drosophila melanogaster.

The P[MTW] transposon carries a functional MtnA (metallothionein) gene and a miniwhite reporter gene. When P[MTW] was transformed into Drosophila, many lines were found to show position-dependent expression patterns of the miniwhite or the MtnA transgene. Identification of several of the target genes indicated that this construct behaves as an enhancer or silencer trap. For instance, expression of at least one reporter transgene was shown to correlate with that of the endogenous gene in the case of insertions in Ultrabithorax, four-jointed, and the iroquois complex. The frequency of patterns recovered with P[MTW] is higher than that reported for P[LacW], suggesting that P[MTW] has unusual properties. The possibility of biased insertion of P[MTW] was assayed by screening a sample of 66 MTW lines for modifiers of the extra sex comb phenotype caused by a hypomorphic allele of polyhomeotic. Seven modifiers were recovered, which could be ranked in two classes: genes involved in leg morphogenesis (including four-jointed and spitz), and genes of the Polycomb- or trithorax-Group, including trithorax and batman, a new gene which encodes a product with a BTB/POZ domain. Taken together, these results indicate that P[MTW] allows the tagging of patterning and cell determination genes, and thus provides a useful tool for identifying new developmental functions.

Animals↗