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We previously used a genetic approach to identify a new class of Schizosaccharomyces pombe genes (chromosome loss when overexpressed; clo genes) that, when present in elevated dosage, cause the loss of an otherwise stable cen1 linear minichromosome at high rates. Here we report the identities of two clo genes; one encodes histone H3.3 and the other, designated clo2, encodes a novel protein with significant homology to fission yeast Swi6p, human and Drosophila HP1 heterochromatin proteins, and other chromo domain-containing proteins. Members of this group have been shown to localize to heterochromatic DNA, including centromeres, and to play roles in chromatin formation and organization. The S. pombe Clo2 protein localizes to centromere DNA in vivo, and overexpression of clo2 leads to a dramatic increase in the rate of mitotic loss of an artificial chromosome. Clo2p is not essential for mitotic growth, however, even in cells that also lack Swi6p. Thus, fission yeast appears to utilize multiple, functionally redundant, HP1-related proteins for heterochromatin-associated activities at centromeres and perhaps elsewhere in the genome.
Mol Gen Genet 2000 Nov
PMID:A novel member of the Swi6p family of fission yeast chromo domain-containing proteins associates with the centromere in vivo and affects chromosome segregation. 1112 54

The SP100 protein, together with PML, represents a major constituent of the PML-SP100 nuclear bodies (NBs). The function of these ubiquitous subnuclear structures, whose integrity is compromised in pathological situations such as acute promyelocytic leukemia (APL) or DNA virus infection, remains poorly understood. There is little evidence for the occurrence of actual physiological processes within NBs. The two NB proteins PML and SP100 are covalently modified by the ubiquitin-related SUMO-1 modifier, and recent work indicates that this modification is critical for the regulation of NB dynamics. In exploring the functional relationships between NBs and chromatin, we have shown previously that SP100 interacts with members of the HP1 family of nonhistone chromosomal proteins and that a variant SP100 cDNA encodes a high-mobility group (HMG1/2) protein. Here we report the isolation of a further cDNA, encoding the SP100C protein, that contains the PHD-bromodomain motif characteristic of chromatin proteins. We further show that TIF1alpha, a chromatin-associated factor with homology to both PML and SP100C, is also modified by SUMO-1. Finally, in vitro experiments indicate that SUMO modification of SP100 enhances the stability of SP100-HP1 complexes. Taken together, our results suggest an association of SP100 and its variants with the chromatin compartment and, further, indicate that SUMO modification may play a regulatory role in the functional interplay between the nuclear bodies and chromatin.
Mol Cell Biol 2001 May
PMID:Common properties of nuclear body protein SP100 and TIF1alpha chromatin factor: role of SUMO modification. 1131 57

The assembly of DNA into regions of inaccessible chromatin, called silent chromatin, is involved in the regulation of gene expression and maintenance of chromosome stability in eukaryotes. Recent studies on Sir2-containing silencing complexes in budding yeast and HP1- and Swi6-containing silencing complexes in metazoans and fission yeast suggest a common mechanism for the assembly of these domains, which involves the physical coupling of histone modifying enzymes to histone binding proteins.
Mol Cell 2001 Sep
PMID:Common themes in mechanisms of gene silencing. 1158 12

The Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome presenting as an association of imperforate anus, triphalangeal and supernumerary thumbs, malformed ears and sensorineural hearing loss. Mutations in SALL1, a gene mapping to 16q12.1, were identified as a cause for TBS. To elucidate how SALL1 mutations lead to TBS, we have performed a series of functional studies with the SALL1 protein. Using epifluorescence and confocal microscopy it could be shown that a GFP-SALL1 fusion protein localizes to chromocenters and smaller heterochromatin foci in transiently transfected NIH-3T3 cells. Chromocenters consist of clustered pericentromeric heterochromatin and contain telomere sequences. Indirect immunofluorescence revealed a partial colocalization of GFP-SALL1 with M31, the mouse homolog of the Drosophila heterochromatic protein HP1. It was further demonstrated that SALL1 acts as a strong transcriptional repressor in mammalian cells. Transcriptional repression could not be relieved by the addition of the histone deacetylase inhibitor Trichostatin-A. In a yeast two-hybrid screen we identified PIN2, an isoform of telomere-repeat-binding factor 1 (TRF1), as an interaction partner of SALL1, and showed that the N-terminus of SALL1 is not necessary for the interaction with PIN2/TRF1. The interaction was confirmed in vitro in a GST-pulldown assay. The association of the developmental regulator SALL1 with heterochromatin is striking and unexpected. Our results propose an involvement of SALL1 in the regulation of higher order chromatin structures and indicate that the protein might be a component of a distinct heterochromatin-dependent silencing process. We have also provided new evidence that there is a close functional link between the centromeric and telomeric heterochromatin domains not only in Drosophila and yeast, but also in mammalian cells.
Hum Mol Genet 2001 Dec 15
PMID:SALL1, the gene mutated in Townes-Brocks syndrome, encodes a transcriptional repressor which interacts with TRF1/PIN2 and localizes to pericentromeric heterochromatin. 1175 84

Methylation of histone H3 at lysine 9 by SUV39H1 and subsequent recruitment of the heterochromatin protein HP1 has recently been linked to gene silencing. In addition to lysine 9, histone H3 methylation also occurs at lysines 4, 27, and 36. Here, we report the purification, molecular identification, and functional characterization of an H3-lysine 4-specific methyltransferase (H3-K4-HMTase), SET7. We demonstrate that SET7 methylates H3-K4 in vitro and in vivo. In addition, we found that methylation of H3-K4 and H3-K9 inhibit each other. Furthermore, H3-K4 and H3-K9 methylation by SET7 and SUV39H1, respectively, have differential effects on subsequent histone acetylation by p300. Thus, our study provides a molecular explanation to the differential effects of H3-K4 and H3-K9 methylation on transcription.
Mol Cell 2001 Dec
PMID:Purification and functional characterization of a histone H3-lysine 4-specific methyltransferase. 1177 97

Mechanism of actinomycin D (AMD) and 7-aminoactinomycin D (7AAMD) interaction with DNA and model nucleotide compounds was studied by absorption and fluorescence spectroscopy (steady-state, phase-modulation, and polarization). It was shown that complex formation does not result in energy transfer from photoexcited nucleotides to phenoxazone chromophore of 7AAMD that indicates the absence of stacking-like intercalation. This fact is fundamentally important to explain the biological effect of actinomycin on cells. It was revealed a fundamental difference in the complex-forming properties of AMD and 7AAMD. Thus AMD is capable of binding to guanine micelles to destroy them. 7AAMD forms complexes neither guanine micelles nor polyguanilic acid. 7AAMD binding sites on DNA can differ substantially from AMD binding sites. However, a strong competition is observed between AMD and 7AAMD for binding site in oligonucleotide HP1 used as DNA hairpin model. The efficient diameters of 7AAMD-HP1 complex and free 7AAMD were determined using the Levshin-Perren equation.
Mol Biol (Mosk)
PMID:[Non stacking binding of 7-amino-actinomycin D and actinomycin D to DNA and model nucleotide systems in solutions]. 1217 79

Genomic imprinting is a form of epigenetic inheritance that is characterized by differential expression of a gene depending on its parental origin. The mini-X chromosome Dp(1;f)LJ9 in Drosophila shows this type of classical imprinting; when transmitted by the maternal parent genes on this chromosome are fully expressed, but when the chromosome is transmitted by the male parent at least three genes are subject to silencing, resulting in a variegated expression pattern. Chemical and environmental modifiers of position-effect variegation have been shown to alter the somatic maintenance of the imprint. To extend these observations, several mutations in chromatin-associated proteins were examined for their effect on imprinting on the Dp(1;f)LJ9 mini-X chromosome. Effects on establishment and maintenance were independently assessed by genetically associating the mutations in chromatin modifiers with the mini-X chromosome in either the parents, where the imprint is established, or the progeny, in which the imprint must be maintained. Nine Suppressor of variegation [ Su(var)] mutations, including alleles of the Su(var)2-5 gene, which encodes the well characterized heterochromatin-associated protein HP1, abolished maintenance but not the establishment of the imprint. Mutant alleles of two genes in the trithorax group ( trx-G), brahma and trithorax, showed a maternal-effect enhancement of the paternal imprint. Surprisingly, however, with the exception of an Enhancer of Polycomb [ E(Pc)] allele, none of the Polycomb-group ( Pc-G) mutations tested affected the imprint. Thus, the maintenance of this imprint relies on the wild-type products of Su(var) and trx-G, but not Pc-G, genes. Finally, none of the mutations tested affected the maintenance of the maternal imprint or the establishment of either the maternal or paternal imprint, suggesting that the maternal and paternal imprints depend on different molecular processes and that imprint establishment and maintenance are independently regulated.
Mol Genet Genomics 2002 Sep
PMID:Genomic imprinting in Drosophila is maintained by the products of Suppressor of variegation and trithorax group, but not Polycomb group, genes. 1224 5

Brazilian purpuric fever (BPF) is a fulminant septicaemic infection of young children, caused by a clonal group of strains of Haemophilus influenzae biogroup aegyptius (Hae), an organism previously solely associated with conjunctivitis. Their special capacity to invade from the initial site of conjunctival infection is unexplained. A polymerase chain reaction (PCR)-amplified subtractive hybridization technique was used to identify genes specific to the BPF clonal group. A copy of bacteriophage HP1 and 46 further chromosomal loci were identified in the BPF but not in the conjunctivitis strain of Hae. Sixteen were characterized further, and one - encoding an analogue of the Legionella pneumophila epithelial cell entry-enhancing protein EnhC - was investigated in depth. Two genes, bpf001 and bpf002, unique to the BPF clonal group were identified between homologues of HI1276 and HI1277 in a complex locus close to H. influenzae genetic island 1, recently identified in pathogenic H. influenzae type b. Bpf001 encodes a protein homologous to EnhC and to the previously uncharacterized product of the meningococcal gene NMB0419. Functional studies of bpf001 proving intractable, NMB0419 was chosen as a surrogate for investigation and shown to modulate bacterial interaction with monolayers of human respiratory epithelial cells, promoting invasion, the first stage (for Hae) in the pathogenesis of BPF.
Mol Microbiol 2003 Feb
PMID:Identification and characterization of genomic loci unique to the Brazilian purpuric fever clonal group of H. influenzae biogroup aegyptius: functionality explored using meningococcal homology. 1258 62

Heritable and reversible changes in gene expression can occur without alterations in DNA sequence largely dependent upon the position of a gene within an accessible (euchromatic) chromatin environment. This position effect variegation in Drosophila and S. pombe, and higher order chromatin structure regulation in yeast, is orchestrated by modifier genes of the Su(var) group (e.g. histone deacetylases (HDACs), protein phosphatases) and enhancer E(var) group (e.g. ATP-dependent nucleosome remodeling proteins). Higher order chromatin structure is regulated in part by covalent modification of the N-terminal histone tails of chromatin and histone tails in turn serve as platforms for recruitment of signaling modules that include non-histone proteins such as HP1 and NuRD. As the enzymes governing chromatin structure through covalent modifications of histones (acetylation, methylation, phosphorylation, ubiquitination) can also target non-histone substrates, a mechanism is in place by which epigenetic regulatory processes can affect the function of these alternate substrates. The nuclear receptor (NR) superfamily consists of conserved modular transcriptional regulators. Herein, we review the functional properties of nuclear receptors regulated by their direct acetylation including ligand-dependent activation, cellular growth and apoptosis.
J Steroid Biochem Mol Biol 2003 Jun
PMID:Nuclear receptor modifications and endocrine cell proliferation. 1294 97

Recent data in yeast and Drosophila suggest a domain-like centromere structure with a modified chromatin core and flanking regions of heterochromatin. We have analyzed a functional human centromere and defined a region of increased chromosome scaffold/matrix attachment that overlaps three other distinct and nonoverlapping domains for constitutive centromere proteins CENP-A and CENP-H, and heterochromatin protein HP1. Transcriptional competency is intact throughout the S/MAR-enriched region and within the CENP-A- and CENP-H-associated chromatin. These results provide insights into the relationship between centromeric chromatin and transcriptional competency in vivo, highlighting the permissibility of transcription within the constitutively modified, nonheterochromatic chromatin of a functional eukaryotic centromere.
Mol Cell 2003 Aug
PMID:Transcription within a functional human centromere. 1453 89


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