Disease relevance of Su(var)205

• Here, we show that in P19 embryonal carcinoma (EC) nuclei, HP1 alpha, beta, and gamma form homo- and heteromers associated with nucleosomal core histones [1].
• A loss of HP1 leads to lethality in Drosophila and correlates with metastasis in human breast cancer cells [2].
• Screening of a lambda gt11 cDNA expression library with one of the monoclonal antibodies identified a recombinant DNA phage clone that produced a fusion protein immunologically similar to the heterochromatin-associated protein [3].
• Human HP1 was expressed as a GST-fusion in Escherichia coli and purified with glutathione-Sepharose [4].
• A 12 kb fragment of Drosophila melanogaster DNA cloned in a lambda phage, lambda T-A, is shown by in situ hybridization to contain sequences homologous to DNA at the extreme ends of each of the polytene chromosomes and to the pericentric sequences present in the beta heterochromatin [5].

High impact information on Su(var)205

• Consistently, JAK loss of function enhances heterochromatic gene silencing, whereas overexpressing HP1 suppresses oncogenic JAK-induced tumors [6].
• Insulator activity is decreased when Argonaute genes required for RNAi are mutated, and insulator function is improved when the levels of the Rm62 helicase, involved in double-stranded RNA (dsRNA)-mediated silencing and heterochromatin formation, are reduced [7].
• Cytological analysis of mitotic chromosomes showed that HP1 depletion caused sex-biased chromosomal defects, including telomere fusions [8].
• Using a Gal4-induced RNA interference system, we showed that conditional depletion of HP1 in transgenic flies resulted in preferential lethality in male flies [8].
• These findings indicate substantial changes in the state of telomeric heterochromatin in SUV39DN cells, which are associated with abnormal telomere elongation [9].

Chemical compound and disease context of Su(var)205

• The flamenco (flam) locus, located at 20A1-3 in the centromeric heterochromatin of the Drosophila melanogaster X chromosome, is a major regulator of the gypsy/mdg4 endogenous retrovirus [10].

Biological context of Su(var)205

• In a screen for genetic modifiers of PDS, we isolated mutations in Su(var)205, Su(var)3-7, and two unidentified genes that suppress this variegated phenotype [11].
• Polycomb is one of a number of genes that are required to prevent ectopic homeotic gene expression in Drosophila, while HP1, the product of the Drosophila melanogaster Su(var)205 gene, is associated with the phenomenon of position effect variegation [12].
• The role of histone H2Av variant replacement and histone H4 acetylation in the establishment of Drosophila heterochromatin [13].
• In Su(var)3-9 null mutants, concentration of HP1 at the chromocentre is nearly lost without affecting HP1 accumulation at the fourth chromosome [14].
• Su(var)3-9 is a dominant modifier of heterochromatin-induced gene silencing [14].

Anatomical context of Su(var)205

• Peptides that interfere with HP1a/HOAP interactions in co-precipitation experiments also displace HP1 from the heterochromatic chromocenter of polytene chromosomes in larval salivary glands [15].
• This analysis showed the expression of 8 different Pc genes in CD34(+) bone marrow cells, including HP1(Hsalpha), HP1(Hsgamma), the heterochromatin p25 protein, the human homologue of the murine M32 gene, and 4 novel members of this family [16].
• Integrating the available information, we also present a hypothetical model describing how HP1, acting as a bifunctional cross-linker, could organize peripheral heterochromatin and contribute in the compartmentalization of the cell nucleus [17].
• We conclude that the major sequence in the polypurine transcript is (ApGpApApGp)n. In situ hybridization to salivary gland polytene chromosomes and to metaphase chromosomes from neural ganglia indicated that polypyrimidines complementary to polypurine RNA are located in heterochromatin [18].
• Drosophila argonaute-2 is required early in embryogenesis for the assembly of centric/centromeric heterochromatin, nuclear division, nuclear migration, and germ-cell formation [19].

Associations of Su(var)205 with chemical compounds

• Association of the highly conserved heterochromatin protein, HP1, with the specialized chromatin of centromeres and telomeres requires binding to a specific histone H3 modification of methylation on lysine 9 [15].
• In this study, we show that a reduction in the levels of the JIL-1 histone H3S10 kinase results in the spreading of the major heterochromatin markers dimethyl H3K9 and HP1 to ectopic locations on the chromosome arms, with the most pronounced increase on the X chromosomes [20].
• This observation suggests that the methyl-binding property of HP1 may not be sufficient for its heterochromatin targeting [21].
• A Distinct Type of Heterochromatin Within Drosophila melanogaster Chromosome 4 [22].
• Methylammonium recognition involves two aromatic residues, not the three-residue aromatic cage used by chromodomains of HP1 and Polycomb proteins [23].

Physical interactions of Su(var)205

• Furthermore, HP1alpha interacts with the linker histone H1 [1].
• Recently, one mechanism of HP1 chromosome association was revealed; the amino-terminal chromo domain of HP1 interacts with methylated lysine nine of histone H3, consistent with the histone code hypothesis [2].
• The lysine 9 position is trimethylated and this mark is closely associated with Polycomb binding sites on polytene chromosomes but is also found in centric heterochromatin, chromosome 4, and telomeric sites [24].
• The GAGA factor of Drosophila is a sequence-specific DNA-binding protein that contributes to multiple processes from the regulation of gene expression to the structural organisation of heterochromatin and chromatin remodelling [25].

Co-localisations of Su(var)205

• In addition to its localization at the chromocentre, in polytene chromosomes, DDP1 is also detected at several sites in the euchromatic arms co-localizing with the heterochromatin protein HP1 [26].
• The SuUR protein, which is involved in the control of chromosome organization, is localized exclusively in heterochromatin and often colocalizes on chromosomes with Polycomb group proteins [27].
• An actin-related protein in Drosophila colocalizes with heterochromatin protein 1 in pericentric heterochromatin [28].

Regulatory relationships of Su(var)205

• In addition SU(Z)12 represses transcription activity in the presence of HP1alpha in a reporter assay [29].
• Chimeric HP1-Polycomb protein expression in transgenic flies promotes heterochromatin-mediated gene silencing, supporting the view that the chromo domain homology reflects a common mechanistic basis for homeotic and heterochromatic silencing [30].
• This study demonstrates that heterochromatin-dependent PEV silencing is also influenced by SuUR [31].
• Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly [32].
• Conferring a function to each of the conserved motives allows us to better understand the mode of action of SU(VAR)3-7 in triggering heterochromatin formation and subsequent genomic silencing [33].

Other interactions of Su(var)205

• A hyperactive Su(var)3-9 mutant, pitkin(D), displays extensive H3-K9 di- and trimethylation within but also outside pericentric heterochromatin [34].
• Whereas the majority of Su(var)s encode inherent components of heterochromatin that can establish repressive chromatin structures [intrinsic Su(var)s], Su(var)3-1 reflects gain-of-function mutants of a euchromatic component that antagonize the expansion of heterochromatic subdomains [acquired Su(var)s] [34].
• Mutations recovered in HP2 act as dominant suppressors of position effect variegation, confirming a role in heterochromatin spreading and gene silencing [35].
• P repression by P strains whose repressive capacities are not linked to the presence of P copies at 1A were previously found to be insensitive to Su(var)205; here, we show that they are also insensitive to aubergine mutations [36].
• We find heterochromatin protein 1/origin recognition complex-associated protein (HOAP) to interact specifically with the originally described predominantly heterochromatic HP1a protein [15].
• These findings implicate a direct interaction between the PIWI-mediated small RNA mechanism and heterochromatin-forming pathways in determining the epigenetic state of the fly genome [37].

Analytical, diagnostic and therapeutic context of Su(var)205

• A PCR generated probe encompassing the HP1 chromo box was used to clone full-length murine cDNAs that contain conserved chromo box motifs [38].
• Sequence comparisons, in situ hybridization experiments, and RNA Northern blot analysis suggest that the murine and human sequences presented in this report are homologues of the Drosophila HP1 gene [38].
• Site-directed mutagenesis within the two conserved regions has shown that the 16 amino acid domain is critical for HP1 binding [39].
• Genetic dissection of heterochromatic gene silencing in position-effect variegation (PEV) by Su(var) and E(var) mutations allowed identification and functional analysis of key factors controlling the formation of heterochromatin [40].
• Supercompact heterochromatin is absent from the telomeres of polytene chromosomes: electron microscopy analysis identifies the telomeric cap and the tract of retroelements as a reticular material, having no discernible banding pattern, whereas TAS repeats appear as faint bands [41].

References