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PubMed2002

Identification and mapping of nuclear matrix-attachment regions in a one megabase locus of human chromosome 19q13.12: long-range correlation of S/MARs and gene positions.

The first draft human genome sequence now available allowed the identification of an enormous number of gene coding areas of the genomic DNA. However, a great number of regulatory elements such as enhancers, promoters, transcription terminators, or replication origins can not be identified unequivocally by their nucleotide sequences in complex eukaryotic genomes. One important subclass of these type of sequences is scaffold/matrix attachment regions (S/MARs) that were hypothesized to anchor chromatin loops or domains to the nuclear matrix and/or chromosome scaffold. We developed an experimental selection procedure to identify S/MARs within a completely sequenced one megabase (1 Mb) long gene-rich D19S208-COX7A1 locus of human chromosome 19. A library of S/MAR elements from the locus was prepared and shown to contain -20 independent S/MARs. Sixteen of them were isolated, sequenced, and assigned to certain positions within the locus. A majority of the S/MARs identified (11 out of 16) lie in intergenic regions, suggesting their structural role, i.e., delimitation of chromatin domains. These 11 S/MARs subdivide the locus into 10 domains ranging from 6 to 272 kb with an average domain size of 88 kb. The remaining five S/MARs were found within intronic sequences of APLP1, HSPOX1, MAG, and NPHS1 genes, and can be tentatively characterized as regulatory S/MARs. The correspondence of the chromatin domains defined by the S/MARs to functional characteristics of the genes therein is discussed. The approach described can be a prototype of a similar search of long sequenced genomic stretches and/or whole chromosomes for various regulatory elements.

Chromosome Mapping↗
PubMed2001

Breakpoints of t(4;11) translocations in the human MLL and AF4 genes in ALL patients are preferentially clustered outside of high-affinity matrix attachment regions.

Chromosomal translocations t(4;11) are based on illegitimate recombinations between the human MLL and AF4 genes, and are associated with high-risk acute leukemias of infants and young children. Here, the question was asked, whether a correlation exists between the location of translocation breakpoints within both genes and the location of S/MARs. In "halo mapping experiments" (to define SARs), about 20 kb of MLL DNA was found to be attached to the nuclear matrix. Similar experiments performed for the translocation partner gene AF4 revealed that SARs are spanning nearly the complete breakpoint cluster region of the AF4 gene. By using short DNA fragments in "scaffold reassociation experiments" (to define MARs), similar results were obtained for both genes. However, Distamycin A competition experiments in combination with "scaffold reassociation experiments" revealed specific differences in the affinity of each tested DNA fragment to bind the isolated nuclear matrix proteins. When the latter data were compared with the known location of chromosomal breakpoints for both genes, an unexpected correlation was observed. DNA areas with strong MAR affinity contained fewer translocation breakpoints, while areas with weak or absent MAR affinity showed a higher density of chromosomal breakpoints.

Chromosome Breakage↗
PubMed1993

Homeodomain protein binding sites, inverted repeats, and nuclear matrix attachment regions along the human beta-globin gene complex.

beta-Globin genes in primates arose during evolution by duplication of an ancestral gene, and their order of arrangement along the DNA is related to their timing of expression during development. We believe that nuclear matrix anchorage sites (MARs) along the beta-globin gene complex considered to be mass binding sites for transcription protein factors, some of which are developmental stage specific and others ubiquitous, play a decisive role in cell memory by determining the developmental stage-specific expression of the genes. The AT-rich class of MARs appears to possess a significant number of ATTA and ATTTA motifs known to be mass binding sites for homeodomain proteins that determine body formation in development. MARs also appear to harbor origins of replication, to be enriched in inverted repeats (dyad symmetry motifs) and were proposed to include the DNase I hypersensitive sites of a particular gene determined at the chromatin level. This study is an attempt to finely identify MARs at the nucleotide level along the beta-globin gene complex. Searches of a contiguous stretch of about 73.3 kb of human sequences comprising and surrounding the epsilon, gamma G-, gamma A-, delta-, and beta-globin genes of the human beta-globin gene complex for homeotic protein binding sites as well as for inverted repeats has shown that these elements are clustered nonrandomly at particular sites within the beta-globin gene complex. These sites are presumed to be the AT-rich class of MARs of the beta-globin gene complex. The inverted repeats which are characteristic of origins of replication and some promoter/enhancer regions and the homeotic protein sites seem to include the DNase I hypersensitive sites of the gene complex. Indeed, dyad symmetry sequences are present close to the four DNase I HS sites in the locus control region (LCR) of the gene complex as well as in the 5' flanking regions and the large introns of the delta- and beta-globin genes. A search of the putative MAR regions of the gene complex suggests that, in addition to their enrichment in ATTA motifs, palindromes, and DNase I hypersensitive sites, these regions may comprise TG-rich motifs and potential Z-DNA as well as polypurine and polypyrimidine blocks. From the positions of palindromes and clusters of homeodomain protein sites along the complex we propose that an extended origin of replication able to initiate at several sites is present in the LCR and two others surrounding the delta- and beta-globin genes.(ABSTRACT TRUNCATED AT 400 WORDS)

Base Sequence↗
PubMed1997

Genetic testing for male infertility: a postulated role for mutations in sperm nuclear matrix attachment regions.

Numerous reports have suggested that disturbances in nuclear condensation may result in male infertility. This notion has been supported by the observation of infertile individuals with a decrease or absence of the male sperm-specific chromatin packaging protamine proteins. To date, no correlation between the absence of protamine proteins and a mutation within the coding regions of the protamine genes has been documented. To address this issue, PCR-based mutation scanning analysis has been performed across the human male haploid expressed PRM1-->PRM2-->TNP2 domain in several oligozoospermic infertile individuals. This analysis identified a candidate mutation in a region of contact with the sperm nuclear matrix from 2 of 5 affected individuals. This is the first report of a mutation scan covering the entire PRM1-->PRM2-->TNP2 locus in affected individuals.

Chromosomal Proteins, Non-Histone↗
PubMed1999

The degradation profile of extrachromosomal circular DNA during cisplatin-induced apoptosis is consistent with preferential cleavage at matrix attachment regions.

Extrachromosomal circular DNA molecules are prevalent in cancer cells and harbor amplified genes, such as oncogenes and drug resistance genes, that can provide a selective growth advantage to cancer cells. These circular DNA structures include double minute chromosomes (dmin), which can be detected with light microscopy following Giemsa staining, and submicroscopic circular DNA structures referred to as episomes. In this study, we investigated the fate of dmin and episomes in multidrug-resistant human epidermoid KB-VI cells undergoing cisplatin-induced apoptosis-a mode of cell death initially characterized by the fragmentation of chromosomal DNA, while the nuclear membrane remains intact. The circular DNA structures carry amplified copies of the multidrug resistance gene (MDR1). During cisplatin-induced apoptotic cell death, episomes and dmin, as well as native chromosomes, were degraded into high molecular weight DNA fragments of approximately 50 kb in length. DNA fragments in this size range appear to result from the preferential cleavage of matrix-associated regions in chromatin with the subsequent release of 20-30 nm loop domains of chromatin from the nuclear scaffold. Scanning electron microscopy studies were performed and confirmed the presence of 30 nm filaments in a higher-order DNA packing of MDR1-containing dmin and episomes. These combined data provide strong evidence that the higher-order DNA packing of episomes, as well as dmin, is similar to that of native chromosomes and underscore the potential for extrachromosomal DNA amplicons to study the structural and functional organization of chromatin. We discuss the implications of extra-chromosomal DNA matrix associated regions competing with native chromosomal DNA for binding to the nuclear matrix in tumor cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Interaction of nuclear proteins with intrinsically curved DNA in a matrix attachment region of a tobacco gene.

Two scaffold/matrix attachment regions (S/MARs), designated S/M I and S/M II, are located in the 5'-flanking region of the tobacco basic class I chitinase gene, CHN50. Structural analysis of these S/MARs showed that S/M II contained an intrinsically curved DNA sequence that is located between -1786 and -1722 relative to the initiation site of transcription. Electrophoretic mobility shift assays and southwestern blotting analysis were performed to identify the tobacco nuclear proteins that bind specifically to this curved DNA. These experiments revealed that nuclear proteins bound specifically to the curved DNA. Moreover, the nuclear proteins appeared to recognize the overall structure of the intrinsically curved DNA, as distinct from binding to the DNA with sequence specificity. Southwestern blotting analysis showed that proteins of 22, 24, 28 and 34 kDa bound specifically to the curved DNA. The possible functions of the binding proteins and their relationship to previously identified nuclear proteins, such as high-mobility-group proteins, are discussed.

Base Sequence↗
PubMed1997

The beta-phaseolin 5' matrix attachment region acts as an enhancer facilitator.

MARs found flanking the beta-phaseolin gene (phas) were tested for insulating activity in an enhancer blocking assay. True insulators should block enhancer dependent expression of a reporter gene when placed between the enhancer and a promoter. Insertion of phas 3' MAR or coding sequences lowered CaMV 35S enhancer driven GUS expression from the phas basal promoter, indicating a distance dependence of the 35S enhancer. 5' MAR or 5' MAR core fragments could not act as independent enhancers when fused to the phas basal promoter, and did not lower expression when inserted in the enhancer blocking assay construct, indicating that they facilitated 35S enhancer expression at a distance when located between the enhancer and the promoter.

Base Sequence↗
PubMed2006

Spatiotemporal expression control correlates with intragenic scaffold matrix attachment regions (S/MARs) in Arabidopsis thaliana.

Scaffold/matrix attachment regions (S/MARs) are essential for structural organization of the chromatin within the nucleus and serve as anchors of chromatin loop domains. A significant fraction of genes in Arabidopsis thaliana contains intragenic S/MAR elements and a significant correlation of S/MAR presence and overall expression strength has been demonstrated. In this study, we undertook a genome scale analysis of expression level and spatiotemporal expression differences in correlation with the presence or absence of genic S/MAR elements. We demonstrate that genes containing intragenic S/MARs are prone to pronounced spatiotemporal expression regulation. This characteristic is found to be even more pronounced for transcription factor genes. Our observations illustrate the importance of S/MARs in transcriptional regulation and the role of chromatin structural characteristics for gene regulation. Our findings open new perspectives for the understanding of tissue- and organ-specific regulation of gene expression.

Arabidopsis↗
PubMed2002

The origin recognition complex marks a replication origin in the human TOP1 gene promoter.

The locations of the origin recognition complex (ORC) in mammalian genomes have been elusive. We have therefore analyzed the DNA sequences associated with human ORC via in vivo cross-linking and chromatin immunoprecipitation. Antibodies specific for hOrc2 protein precipitate chromatin fragments that also contain other ORC proteins, suggesting that the proteins form multisubunit complexes on chromatin in vivo. A binding region for ORC was identified at the CpG island upstream of the human TOP1 gene. Nascent strand abundance assays show that the ORC binding region coincides with an origin of bidirectional replication. The TOP1 gene includes two well characterized matrix attachment regions. The matrix attachment region elements analyzed contain no ORC and constitute no sites for replication initiation. In initial attempts to use the chromatin immunoprecipitation technique for the identification of additional ORC sites in the human genome, we isolated a sequence close to another actively transcribed gene (TOM1) and an alphoid satellite sequence that underlies centromeric heterochromatin. Nascent strand abundance assays gave no indication that the heterochromatin sequence serves as a replication initiation site, suggesting that an ORC on this site may perform functions other than replication initiation.

Base Sequence↗
PubMed2001

Characterisation and high-resolution distribution of a matrix attachment region-binding protein (MFP1) in proliferating cells of onion.

The first matrix attachment region (MAR)-binding protein sequenced in plants, MFP1, has been characterised in two dicot species. Based on their antigenic relationship, we report here the conservation of MFP1-like proteins in proliferating root cells of onion (Allium cepa L). Two MFP1-like proteins with different molecular masses and solubilities were detected. The most abundant was a 90-kDa basic protein, presenting several separate spots in two-dimensional blots. The MFP1 was partially soluble and, similar to the proliferating cell nuclear antigen (PCNA)-labelled replication factories in the nucleus and nuclear matrix, was localised at discrete foci as detected by confocal microscopy. High-resolution immunolocalisation of MFP1 by electron microscopy identified the foci as nuclear structures, some of them containing PCNA, which are ultrastructurally similar to the replication factories described in animal cells. Our data provide the first report on MFP1-like proteins in the Alliaceae. In addition, we present evidence of the presence of AcMFP1 in the putative replication factories.

Arabidopsis Proteins↗