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1
Matveevsky, Sergey, Oxana Kolomiets, Aleksey Bogdanov, Elena Alpeeva und Irina Bakloushinskaya. „Meiotic Chromosome Contacts as a Plausible Prelude for Robertsonian Translocations“. Genes 11, Nr. 4 (02.04.2020): 386. http://dx.doi.org/10.3390/genes11040386.
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Robertsonian translocations are common chromosomal alterations. Chromosome variability affects human health and natural evolution. Despite the significance of such mutations, no mechanisms explaining the emergence of such translocations have yet been demonstrated. Several models have explored possible changes in interphase nuclei. Evidence for non-homologous chromosomes end joining in meiosis is scarce, and is often limited to uncovering mechanisms in damaged cells only. This study presents a primarily qualitative analysis of contacts of non-homologous chromosomes by short arms, during meiotic prophase I in the mole vole, Ellobius alaicus, a species with a variable karyotype, due to Robertsonian translocations. Immunocytochemical staining of spermatocytes demonstrated the presence of four contact types for non-homologous chromosomes in meiotic prophase I: (1) proximity, (2) touching, (3) anchoring/tethering, and (4) fusion. Our results suggest distinct mechanisms for chromosomal interactions in meiosis. Thus, we propose to change the translocation mechanism model from ‘contact first’ to ‘contact first in meiosis’.
2
George, Phillip, Nicholas A. Kinney, Jiangtao Liang, Alexey V. Onufriev und Igor V. Sharakhov. „Three-dimensional Organization of Polytene Chromosomes in Somatic and Germline Tissues of Malaria Mosquitoes“. Cells 9, Nr. 2 (01.02.2020): 339. http://dx.doi.org/10.3390/cells9020339.
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Spatial organization of chromosome territories and interactions between interphase chromosomes themselves, as well as with the nuclear periphery, play important roles in epigenetic regulation of the genome function. However, the interplay between inter-chromosomal contacts and chromosome-nuclear envelope attachments in an organism’s development is not well-understood. To address this question, we conducted microscopic analyses of the three-dimensional chromosome organization in malaria mosquitoes. We employed multi-colored oligonucleotide painting probes, spaced 1 Mb apart along the euchromatin, to quantitatively study chromosome territories in larval salivary gland cells and adult ovarian nurse cells of Anopheles gambiae, An. coluzzii, and An. merus. We found that the X chromosome territory has a significantly smaller volume and is more compact than the autosomal arm territories. The number of inter-chromosomal, and the percentage of the chromosome–nuclear envelope, contacts were conserved among the species within the same cell type. However, the percentage of chromosome regions located at the nuclear periphery was typically higher, while the number of inter-chromosomal contacts was lower, in salivary gland cells than in ovarian nurse cells. The inverse correlation was considerably stronger for the autosomes. Consistent with previous theoretical arguments, our data indicate that, at the genome-wide level, there is an inverse relationship between chromosome-nuclear envelope attachments and chromosome–chromosome interactions, which is a key feature of the cell type-specific nuclear architecture.
3
Miermans, Christiaan A., und Chase P. Broedersz. „Bacterial chromosome organization by collective dynamics of SMC condensins“. Journal of The Royal Society Interface 15, Nr. 147 (Oktober 2018): 20180495. http://dx.doi.org/10.1098/rsif.2018.0495.
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A prominent organizational feature of bacterial chromosomes was revealed by Hi-C experiments, indicating anomalously high contacts between the left and right chromosomal arms. These long-range contacts have been attributed to various nucleoid-associated proteins, including the ATPase Structural Maintenance of Chromosomes (SMC) condensin. Although the molecular structure of these ATPases has been mapped in detail, it still remains unclear by which physical mechanisms they collectively generate long-range chromosomal contacts. Here, we develop a computational model that captures the subtle interplay between molecular-scale activity of slip-links and large-scale chromosome organization. We first consider a scenario in which the ATPase activity of slip-links regulates their DNA-recruitment near the origin of replication, while the slip-link dynamics is assumed to be diffusive. We find that such diffusive slip-links can collectively organize the entire chromosome into a state with aligned arms, but not within physiological constraints. However, slip-links that include motor activity are far more effective at organizing the entire chromosome over all length-scales. The persistence of motor slip-links at physiological densities can generate large, nested loops and drive them into the bulk of the DNA. Finally, our model with motor slip-links can quantitatively account for the rapid arm–arm alignment of chromosomal arms observed in vivo .
4
Socol, Marius, Renjie Wang, Daniel Jost, Pascal Carrivain, Cédric Vaillant, Eric Le Cam, Vincent Dahirel et al. „Rouse model with transient intramolecular contacts on a timescale of seconds recapitulates folding and fluctuation of yeast chromosomes“. Nucleic Acids Research 47, Nr. 12 (22.05.2019): 6195–207. http://dx.doi.org/10.1093/nar/gkz374.
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Abstract DNA folding and dynamics along with major nuclear functions are determined by chromosome structural properties, which remain, thus far, elusive in vivo. Here, we combine polymer modeling and single particle tracking experiments to determine the physico-chemical parameters of chromatin in vitro and in living yeast. We find that the motion of reconstituted chromatin fibers can be recapitulated by the Rouse model using mechanical parameters of nucleosome arrays deduced from structural simulations. Conversely, we report that the Rouse model shows some inconsistencies to analyze the motion and structural properties inferred from yeast chromosomes determined with chromosome conformation capture techniques (specifically, Hi-C). We hence introduce the Rouse model with Transient Internal Contacts (RouseTIC), in which random association and dissociation occurs along the chromosome contour. The parametrization of this model by fitting motion and Hi-C data allows us to measure the kinetic parameters of the contact formation reaction. Chromosome contacts appear to be transient; associated to a lifetime of seconds and characterized by an attractive energy of –0.3 to –0.5 kBT. We suggest attributing this energy to the occurrence of histone tail-DNA contacts and notice that its amplitude sets chromosomes in ‘theta’ conditions, in which they are poised for compartmentalization and phase separation.
5
Benedetti, Fabrizio, Julien Dorier, Yannis Burnier und Andrzej Stasiak. „Models that include supercoiling of topological domains reproduce several known features of interphase chromosomes“. Nucleic Acids Research 42, Nr. 5 (22.12.2013): 2848–55. http://dx.doi.org/10.1093/nar/gkt1353.
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Abstract Understanding the structure of interphase chromosomes is essential to elucidate regulatory mechanisms of gene expression. During recent years, high-throughput DNA sequencing expanded the power of chromosome conformation capture (3C) methods that provide information about reciprocal spatial proximity of chromosomal loci. Since 2012, it is known that entire chromatin in interphase chromosomes is organized into regions with strongly increased frequency of internal contacts. These regions, with the average size of ∼1 Mb, were named topological domains. More recent studies demonstrated presence of unconstrained supercoiling in interphase chromosomes. Using Brownian dynamics simulations, we show here that by including supercoiling into models of topological domains one can reproduce and thus provide possible explanations of several experimentally observed characteristics of interphase chromosomes, such as their complex contact maps.
6
Kranas, Hanna, Irina Tuszynska und Bartek Wilczynski. „HiCEnterprise: identifying long range chromosomal contacts in Hi-C data“. PeerJ 9 (26.04.2021): e10558. http://dx.doi.org/10.7717/peerj.10558.
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Motivation Computational analysis of chromosomal contact data is currently gaining popularity with the rapid advance in experimental techniques providing access to a growing body of data. An important problem in this area is the identification of long range contacts between distinct chromatin regions. Such loops were shown to exist at different scales, either mediating relatively short range interactions between enhancers and promoters or providing interactions between much larger, distant chromosome domains. A proper statistical analysis as well as availability to a wide research community are crucial in a tool for this task. Results We present HiCEnterprise, a first freely available software tool for identification of long range chromatin contacts not only between small regions, but also between chromosomal domains. It implements four different statistical tests for identification of significant contacts for user defined regions or domains as well as necessary functions for input, output and visualization of chromosome contacts. Availability The software and the corresponding documentation are available at: github.com/regulomics/HiCEnterprise. Supplementary information Supplemental data are available in the online version of the article and at the website regulomics.mimuw.edu.pl/wp/hicenterprise.
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Orlov, Y. L., O. Thierry, A. G. Bogomolov, A. V. Tsukanov, E. V. Kulakova, E. R. Galieva, A. O. Bragin und G. Li. „Computer methods of analysis of chromosome contacts in the cell nucleus based on sequencing technology data“. Biomeditsinskaya Khimiya 63, Nr. 5 (2017): 418–22. http://dx.doi.org/10.18097/pbmc20176305418.
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The study spatial chromosome structure and chromosome folding in the interphase cell nucleus is an important challenge of world science. Detection of eukaryotic genome regions that physically interact with each other could be done by modern sequencing technologies. A basic method of chromosome folding by total sequencing of contacting DNA fragments is HI-C. Long-range chromosomal interactions play an important role in gene transcription and regulation. The study of chromosome interactions, 3D (three-dimensional) genome structure and its effect on gene transcription allows revealing fundamental biological processes from a viewpoint of structural regulation and are important for cancer research. The technique of chromatin immunoprecipitation and subsequent sequencing (ChIP-seq) make possible to determine binding sites of transcription factors that regulate expression of eukaryotic genes; genome transcription factors binding maps have been. The ChIA-PET technology allows exploring not only target protein binding sites, but also pairs of such sites on proximally located and interacting with each other chromosomes co-located in three-dimensional space of the cell nucleus. Here we discuss the principles of the construction of genomic maps and matrices of chromosome contacts according to ChIA-PET and Hi-C data that capture the chromosome conformation and overview existing software for 3D genome analysis including in house programs of gene location analysis in topological domains.
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Loidl, Josef. „The initiation of meiotic chromosome pairing: the cytological view“. Genome 33, Nr. 6 (01.12.1990): 759–78. http://dx.doi.org/10.1139/g90-115.
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Opposing views are held with respect to the time when and the mechanisms whereby homologous chromosomes find each other for meiotic synapsis. On the one hand, some evidence has been presented for somatic homologous associations or some other kind of relationship between chromosomes in somatic cells as a preliminary to meiotic pairing. On the other hand, it is argued by many that homologous contacts are first established at meiotic prophase prior to, or in the course of, synaptonemal complex formation. The present paper reviews the controversial cytological evidence, hypotheses, and ideas on how the first contact between homologous chromosomes comes about.Key words: synapsis, meiosis, presynaptic alignment, homologous recognition, synaptonemal complex, chromosome pairing.
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Stodola, Timothy J., Pengyuan Liu, Yong Liu, Andrew K. Vallejos, Aron M. Geurts, Andrew S. Greene und Mingyu Liang. „Genome-wide map of proximity linkage to renin proximal promoter in rat“. Physiological Genomics 50, Nr. 5 (01.05.2018): 323–31. http://dx.doi.org/10.1152/physiolgenomics.00132.2017.
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A challenge to understanding enhancer-gene relationships is that enhancers are not always sequentially close to the gene they regulate. Physical proximity mapping through sequencing can provide an unbiased view of the chromatin close to the proximal promoter of the renin gene ( Ren). Our objective was to determine genomic regions that physically interact with the renin proximal promoter, using two different genetic backgrounds, the Dahl salt sensitive and normotensive SS-13BN, which have been shown to have different regulation of plasma renin in vivo. The chromatin conformation capture method with sequencing focused at the Ren proximal promoter in rat-derived cardiac endothelial cells was used. Cells were fixed, chromatin close to the Ren promoter was captured, and fragments were sequenced. The clustering of mapped reads produced a genome-wide map of chromatin in contact with the Ren promoter. The largest number of contacts was found on chromosome 13, the chromosome with Ren, and contacts were found on all other chromosomes except chromosome X. These contacts were significantly enriched with genes positively correlated with Ren expression and with mapped quantitative trait loci associated with blood pressure, cardiovascular, and renal phenotypes. The results were reproducible in an independent biological replicate. The findings reported here represent the first map between a critical cardiovascular gene and physical interacting loci throughout the genome and will provide the basis for several new directions of research.
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Jian, Xing, und Gary Felsenfeld. „Insulin promoter in human pancreatic β cells contacts diabetes susceptibility loci and regulates genes affecting insulin metabolism“. Proceedings of the National Academy of Sciences 115, Nr. 20 (30.04.2018): E4633—E4641. http://dx.doi.org/10.1073/pnas.1803146115.
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Both type 1 and type 2 diabetes involve a complex interplay between genetic, epigenetic, and environmental factors. Our laboratory has been interested in the physical interactions, in nuclei of human pancreatic β cells, between the insulin (INS) gene and other genes that are involved in insulin metabolism. We have identified, using Circularized Chromosome Conformation Capture (4C), many physical contacts in a human pancreatic β cell line between the INS promoter on chromosome 11 and sites on most other chromosomes. Many of these contacts are associated with type 1 or type 2 diabetes susceptibility loci. To determine whether physical contact is correlated with an ability of the INS locus to affect expression of these genes, we knock down INS expression by targeting the promoter; 259 genes are either up or down-regulated. Of these, 46 make physical contact with INS. We analyze a subset of the contacted genes and show that all are associated with acetylation of histone H3 lysine 27, a marker of actively expressed genes. To demonstrate the usefulness of this approach in revealing regulatory pathways, we identify from among the contacted sites the previously uncharacterized gene SSTR5-AS1 and show that it plays an important role in controlling the effect of somatostatin-28 on insulin secretion. These results are consistent with models in which clustering of genes supports transcriptional activity. This may be a particularly important mechanism in pancreatic β cells and in other cells where a small subset of genes is expressed at high levels.
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Naranjo, Tomás. „Finding the Correct Partner: The Meiotic Courtship“. Scientifica 2012 (2012): 1–14. http://dx.doi.org/10.6064/2012/509073.
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Homologous chromosomes are usually separated at the entrance of meiosis; how they become paired is one of the outstanding mysteries of the meiotic process. Reduction of spacing between homologues makes possible the occurrence of chromosomal interactions leading to homology detection and the formation of bivalents. In many organisms, telomere-led chromosome movements are generated that bring homologues together. Additional movements produced by chromatin conformational changes at early meiosis may also facilitate homologous contacts. Organisms used in the study of meiosis show a surprising variety of strategies for homology detection. In dipterans, homologous chromosomes remain paired throughout most of development. Pairing seems to arise as a balance between promoter and suppressor pairing genes. Some fungi, plants and animals, use mechanisms based on recombinational interactions. Other mechanisms leading to homology search are recombination-independent and require specialized pairing sites. In the wormCaenorhabditis elegans, each chromosome carries a pairing center consisting of a chromosome-specific DNA-protein complex, and in the fission yeastSchizosaccharomyces pombe, thesme2locus encodes a meiosis-specific non-coding RNA that mediates on homologous recognition. In addition, mismatch correction plays a relevant role, especially in polyploids, which evolved genetic systems that suppress pairing between non-homologous related (homoeologus) chromosomes.
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Liu, Lei, Bokai Zhang und Changbong Hyeon. „Extracting multi-way chromatin contacts from Hi-C data“. PLOS Computational Biology 17, Nr. 12 (06.12.2021): e1009669. http://dx.doi.org/10.1371/journal.pcbi.1009669.
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There is a growing realization that multi-way chromatin contacts formed in chromosome structures are fundamental units of gene regulation. However, due to the paucity and complexity of such contacts, it is challenging to detect and identify them using experiments. Based on an assumption that chromosome structures can be mapped onto a network of Gaussian polymer, here we derive analytic expressions for n-body contact probabilities (n > 2) among chromatin loci based on pairwise genomic contact frequencies available in Hi-C, and show that multi-way contact probability maps can in principle be extracted from Hi-C. The three-body (triplet) contact probabilities, calculated from our theory, are in good correlation with those from measurements including Tri-C, MC-4C and SPRITE. Maps of multi-way chromatin contacts calculated from our analytic expressions can not only complement experimental measurements, but also can offer better understanding of the related issues, such as cell-line dependent assemblies of multiple genes and enhancers to chromatin hubs, competition between long-range and short-range multi-way contacts, and condensates of multiple CTCF anchors.
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Tchurikov, Nickolai A., Elena S. Klushevskaya, Daria M. Fedoseeva, Ildar R. Alembekov, Galina I. Kravatskaya, Vladimir R. Chechetkin, Yuri V. Kravatsky und Olga V. Kretova. „Dynamics of Whole-Genome Contacts of Nucleoli in Drosophila Cells Suggests a Role for rDNA Genes in Global Epigenetic Regulation“. Cells 9, Nr. 12 (03.12.2020): 2587. http://dx.doi.org/10.3390/cells9122587.
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Chromosomes are organized into 3D structures that are important for the regulation of gene expression and differentiation. Important role in formation of inter-chromosome contacts play rDNA clusters that make up nucleoli. In the course of differentiation, heterochromatization of rDNA units in mouse cells is coupled with the repression or activation of different genes. Furthermore, the nucleoli of human cells shape the direct contacts with genes that are involved in differentiation and cancer. Here, we identified and categorized the genes located in the regions where rDNA clusters make frequent contacts. Using a 4C approach, we demonstrate that in Drosophila S2 cells, rDNA clusters form contacts with genes that are involved in chromosome organization and differentiation. Heat shock treatment induces changes in the contacts between nucleoli and hundreds of genes controlling morphogenesis. We show that nucleoli form contacts with regions that are enriched with active or repressive histone marks and where small non-coding RNAs are mapped. These data indicate that rDNA contacts are involved in the repression and activation of gene expression and that rDNA clusters orchestrate large groups of Drosophila genes involved in differentiation.
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Champion, Lysie, Sumit Pawar, Naemi Luithle, Rosemarie Ungricht und Ulrike Kutay. „Dissociation of membrane–chromatin contacts is required for proper chromosome segregation in mitosis“. Molecular Biology of the Cell 30, Nr. 4 (15.02.2019): 427–40. http://dx.doi.org/10.1091/mbc.e18-10-0609.
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The nuclear envelope (NE) aids in organizing the interphase genome by tethering chromatin to the nuclear periphery. During mitotic entry, NE–chromatin contacts are broken. Here, we report on the consequences of impaired NE removal from chromatin for cell division of human cells. Using a membrane–chromatin tether that cannot be dissociated when cells enter mitosis, we show that a failure in breaking membrane–chromatin interactions impairs mitotic chromatin organization, chromosome segregation and cytokinesis, and induces an aberrant NE morphology in postmitotic cells. In contrast, chromosome segregation and cell division proceed successfully when membrane attachment to chromatin is induced during metaphase, after chromosomes have been singularized and aligned at the metaphase plate. These results indicate that the separation of membranes and chromatin is critical during prometaphase to allow for proper chromosome compaction and segregation. We propose that one cause of these defects is the multivalency of membrane–chromatin interactions.
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Zhuravlev, Aleksandr V., Gennadii A. Zakharov, Ekaterina V. Anufrieva, Anna V. Medvedeva, Ekaterina A. Nikitina und Elena V. Savvateeva-Popova. „Chromatin Structure and “DNA Sequence View”: The Role of Satellite DNA in Ectopic Pairing of the Drosophila X Polytene Chromosome“. International Journal of Molecular Sciences 22, Nr. 16 (13.08.2021): 8713. http://dx.doi.org/10.3390/ijms22168713.
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Chromatin 3D structure plays a crucial role in regulation of gene activity. Previous studies have envisioned spatial contact formations between chromatin domains with different epigenetic properties, protein compositions and transcription activity. This leaves specific DNA sequences that affect chromosome interactions. The Drosophila melanogaster polytene chromosomes are involved in non-allelic ectopic pairing. The mutant strain agnts3, a Drosophila model for Williams–Beuren syndrome, has an increased frequency of ectopic contacts (FEC) compared to the wild-type strain Canton-S (CS). Ectopic pairing can be mediated by some specific DNA sequences. In this study, using our Homology Segment Analysis software, we estimated the correlation between FEC and frequency of short matching DNA fragments (FMF) for all sections of the X chromosome of Drosophila CS and agnts3 strains. With fragment lengths of 50 nucleotides (nt), CS showed a specific FEC–FMF correlation for 20% of the sections involved in ectopic contacts. The correlation was unspecific in agnts3, which may indicate the alternative epigenetic mechanisms affecting FEC in the mutant strain. Most of the fragments that specifically contributed to FMF were related to 1.688 or 372-bp middle repeats. Thus, middle repetitive DNA may serve as an organizer of ectopic pairing.
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Conin, Brenna, Ingrid Billault-Chaumartin, Hafez El Sayyed, Nicole Quenech’Du, Charlotte Cockram, Romain Koszul und Olivier Espéli. „Extended sister-chromosome catenation leads to massive reorganization of the E. coli genome“. Nucleic Acids Research 50, Nr. 5 (25.02.2022): 2635–50. http://dx.doi.org/10.1093/nar/gkac105.
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Abstract In bacteria, chromosome segregation occurs progressively from the origin to terminus within minutes of replication of each locus. Between replication and segregation, sister loci are held in an apparent cohesive state by topological links. The decatenation activity of topoisomerase IV (Topo IV) is required for segregation of replicated loci, yet little is known about the structuring of the chromosome maintained in a cohesive state. In this work, we investigated chromosome folding in cells with altered decatenation activities. Within minutes after Topo IV inactivation, massive chromosome reorganization occurs, associated with increased in contacts between nearby loci, likely trans-contacts between sister chromatids, and in long-range contacts between the terminus and distant loci. We deciphered the respective roles of Topo III, MatP and MukB when TopoIV activity becomes limiting. Topo III reduces short-range inter-sister contacts suggesting its activity near replication forks. MatP, the terminus macrodomain organizing system, and MukB, the Escherichia coli SMC, promote long-range contacts with the terminus. We propose that the large-scale conformational changes observed under these conditions reveal defective decatenation attempts involving the terminus area. Our results support a model of spatial and temporal partitioning of the tasks required for sister chromosome segregation.
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Mach, Pia, Pavel I. Kos, Yinxiu Zhan, Julie Cramard, Simon Gaudin, Jana Tünnermann, Edoardo Marchi et al. „Cohesin and CTCF control the dynamics of chromosome folding“. Nature Genetics 54, Nr. 12 (Dezember 2022): 1907–18. http://dx.doi.org/10.1038/s41588-022-01232-7.
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AbstractIn mammals, interactions between sequences within topologically associating domains enable control of gene expression across large genomic distances. Yet it is unknown how frequently such contacts occur, how long they last and how they depend on the dynamics of chromosome folding and loop extrusion activity of cohesin. By imaging chromosomal locations at high spatial and temporal resolution in living cells, we show that interactions within topologically associating domains are transient and occur frequently during the course of a cell cycle. Interactions become more frequent and longer in the presence of convergent CTCF sites, resulting in suppression of variability in chromosome folding across time. Supported by physical models of chromosome dynamics, our data suggest that CTCF-anchored loops last around 10 min. Our results show that long-range transcriptional regulation might rely on transient physical proximity, and that cohesin and CTCF stabilize highly dynamic chromosome structures, facilitating selected subsets of chromosomal interactions.
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Hochstrasser, M., D. Mathog, Y. Gruenbaum, H. Saumweber und J. W. Sedat. „Spatial organization of chromosomes in the salivary gland nuclei of Drosophila melanogaster.“ Journal of Cell Biology 102, Nr. 1 (01.01.1986): 112–23. http://dx.doi.org/10.1083/jcb.102.1.112.
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Using a computer-based system for model building and analysis, three-dimensional models of 24 Drosophila melanogaster salivary gland nuclei have been constructed from optically or physically sectioned glands, allowing several generalizations about chromosome folding and packaging in these nuclei. First and most surprising, the prominent coiling of the chromosomes is strongly chiral, with right-handed gyres predominating. Second, high frequency appositions between certain loci and the nuclear envelope appear almost exclusively at positions of intercalary heterochromatin; in addition, the chromocenter is always apposed to the envelope. Third, chromosomes are invariably separated into mutually exclusive spatial domains while usually extending across the nucleus in a polarized (Rabl) orientation. Fourth, the arms of each autosome are almost always juxtaposed, but no other relative arm positions are strongly favored. Finally, despite these nonrandom structural features, each chromosome is found to fold into a wide variety of different configurations. In addition, a set of nuclei has been analyzed in which the normally aggregrated centromeric regions of the chromosomes are located far apart from one another. These nuclei have the same architectural motifs seen in normal nuclei. This implies that such characteristics as separate chromosome domains and specific chromosome-nuclear envelope contacts are largely independent of the relative placement of the different chromosomes within the nucleus.
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Ng, Cai Tong, Li Deng, Chen Chen, Hong Hwa Lim, Jian Shi, Uttam Surana und Lu Gan. „Electron cryotomography analysis of Dam1C/DASH at the kinetochore–spindle interface in situ“. Journal of Cell Biology 218, Nr. 2 (30.11.2018): 455–73. http://dx.doi.org/10.1083/jcb.201809088.
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In dividing cells, depolymerizing spindle microtubules move chromosomes by pulling at their kinetochores. While kinetochore subcomplexes have been studied extensively in vitro, little is known about their in vivo structure and interactions with microtubules or their response to spindle damage. Here we combine electron cryotomography of serial cryosections with genetic and pharmacological perturbation to study the yeast chromosome segregation machinery in vivo. Each kinetochore microtubule has one (rarely, two) Dam1C/DASH outer kinetochore assemblies. Dam1C/DASH contacts the microtubule walls and does so with its flexible “bridges”; there are no contacts with the protofilaments’ curved tips. In metaphase, ∼40% of the Dam1C/DASH assemblies are complete rings; the rest are partial rings. Ring completeness and binding position along the microtubule are sensitive to kinetochore attachment and tension, respectively. Our study and those of others support a model in which each kinetochore must undergo cycles of conformational change to couple microtubule depolymerization to chromosome movement.
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Parl, Fritz F., William D. Dupont und Philip S. Crooke. „Interchromosomal Translocations as a Means to Map Chromosome Territories in Breast Cancer“. Cancer Informatics 18 (Januar 2019): 117693511984257. http://dx.doi.org/10.1177/1176935119842573.
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The genome-wide identification of mutated genes is an important advance in our understanding of tumor biology, but several fundamental questions remain open. How do these genes act together to promote cancer development and, a related question, how are they spatially arranged in the nucleus to allow coordinated expression? We examined the nuclear topography of mutated genes in breast cancer and their relation to chromosome territories (CTs). We performed a literature review and analyzed 1 type of mutation, interchromosomal translocations, in 1546 primary breast cancers to infer the spatial arrangement of chromosomes. The cosegregation of all observed fusion genes was used to create a matrix of genome-wide CT contacts and develop a tentative CT map of breast cancer. Regression analysis was performed to determine the association between CTs and all types of mutations. Chromosomes 17, 11, 8, and 1 had the majority of interchromosomal fusions and are presumably clustered in the nuclear center, whereas chromosomes 22, 21, X, and 18 had the lowest number of contacts, likely reflecting a more peripheral position. Regression analysis revealed that there was no significant association between chromosome length indicated by the number of base pairs per chromosome and the number of total (inter- and intrachromosomal) translocations, point mutations, or copy number aberrations (CNAs). The gene density of chromosomes (genes/Mb) was significantly correlated with total translocations ( P = .02), but not with point mutations P = .19 and CNAs P = .62. Finally, the association of the 3 genetic alterations with the CT map deduced from the interchromosomal fusions was significant, ie, total translocations P = 7 × 10−11, point mutations P = .01, CNAs P = .002. In conclusion, we developed a tentative CT map and observed a spatial association with genetic alterations in breast cancer.
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Matveevsky, Sergey, Irina Bakloushinskaya, Valentina Tambovtseva, Maret Atsaeva, Tatiana Grishaeva, Aleksey Bogdanov und Oxana Kolomiets. „Nonhomologous Chromosome Interactions in Prophase I: Dynamics of Bizarre Meiotic Contacts in the Alay Mole Vole Ellobius alaicus (Mammalia, Rodentia)“. Genes 13, Nr. 12 (23.11.2022): 2196. http://dx.doi.org/10.3390/genes13122196.
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Nonhomologous chromosome interactions take place in both somatic and meiotic cells. Prior to this study, we had discovered special contacts through the SYCP3 (synaptonemal complex protein 3) filament between the short arms of nonhomologous acrocentrics at the pachytene stage in the Alay mole vole, and these contacts demonstrate several patterns from proximity to the complete fusion stage. Here, we investigated the nonhomologous chromosome contacts in meiotic prophase I. It turned out that such contacts do not introduce changes into the classic distribution of DNA double-strand breaks. It is noteworthy that not all meiotic contacts were localized in the H3k9me3-positive heterochromatic environment. Both in the mid zygotene and in the early–mid diplotene, three types of contacts (proximity, touching, and anchoring/tethering) were observed, whereas fusion seems to be characteristic only for pachytene. The number of contacts in the mid pachytene is significantly higher than that in the zygotene, and the distance between centromeres in nonhomologous contacts is also the smallest in mid pachytene for all types of contacts. Thus, this work provides a new insight into the behavior of meiotic contacts during prophase I and points to avenues of further research.
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Val, Marie-Eve, Martial Marbouty, Francisco de Lemos Martins, Sean P. Kennedy, Harry Kemble, Michael J. Bland, Christophe Possoz, Romain Koszul, Ole Skovgaard und Didier Mazel. „A checkpoint control orchestrates the replication of the two chromosomes of Vibrio cholerae“. Science Advances 2, Nr. 4 (April 2016): e1501914. http://dx.doi.org/10.1126/sciadv.1501914.
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Bacteria with multiple chromosomes represent up to 10% of all bacterial species. Unlike eukaryotes, these bacteria use chromosome-specific initiators for their replication. In all cases investigated, the machineries for secondary chromosome replication initiation are of plasmid origin. One of the important differences between plasmids and chromosomes is that the latter replicate during a defined period of the cell cycle, ensuring a single round of replication per cell. Vibrio cholerae carries two circular chromosomes, Chr1 and Chr2, which are replicated in a well-orchestrated manner with the cell cycle and coordinated in such a way that replication termination occurs at the same time. However, the mechanism coordinating this synchrony remains speculative. We investigated this mechanism and revealed that initiation of Chr2 replication is triggered by the replication of a 150-bp locus positioned on Chr1, called crtS. This crtS replication–mediated Chr2 replication initiation mechanism explains how the two chromosomes communicate to coordinate their replication. Our study reveals a new checkpoint control mechanism in bacteria, and highlights possible functional interactions mediated by contacts between two chromosomes, an unprecedented observation in bacteria.
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Nakabayashi, Ryo, und Shinichi Morishita. „HiC-Hiker: a probabilistic model to determine contig orientation in chromosome-length scaffolds with Hi-C“. Bioinformatics 36, Nr. 13 (05.05.2020): 3966–74. http://dx.doi.org/10.1093/bioinformatics/btaa288.
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Abstract Motivation De novo assembly of reference-quality genomes used to require enormously laborious tasks. In particular, it is extremely time-consuming to build genome markers for ordering assembled contigs along chromosomes; thus, they are only available for well-established model organisms. To resolve this issue, recent studies demonstrated that Hi-C could be a powerful and cost-effective means to output chromosome-length scaffolds for non-model species with no genome marker resources, because the Hi-C contact frequency between a pair of two loci can be a good estimator of their genomic distance, even if there is a large gap between them. Indeed, state-of-the-art methods such as 3D-DNA are now widely used for locating contigs in chromosomes. However, it remains challenging to reduce errors in contig orientation because shorter contigs have fewer contacts with their neighboring contigs. These orientation errors lower the accuracy of gene prediction, read alignment, and synteny block estimation in comparative genomics. Results To reduce these contig orientation errors, we propose a new algorithm, named HiC-Hiker, which has a firm grounding in probabilistic theory, rigorously models Hi-C contacts across contigs, and effectively infers the most probable orientations via the Viterbi algorithm. We compared HiC-Hiker and 3D-DNA using human and worm genome contigs generated from short reads, evaluated their performances, and observed a remarkable reduction in the contig orientation error rate from 4.3% (3D-DNA) to 1.7% (HiC-Hiker). Our algorithm can consider long-range information between distal contigs and precisely estimates Hi-C read contact probabilities among contigs, which may also be useful for determining the ordering of contigs. Availability and implementation HiC-Hiker is freely available at: https://github.com/ryought/hic_hiker.
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Kos, Pavel I., Aleksandra A. Galitsyna, Sergey V. Ulianov, Mikhail S. Gelfand, Sergey V. Razin und Alexander V. Chertovich. „Perspectives for the reconstruction of 3D chromatin conformation using single cell Hi-C data“. PLOS Computational Biology 17, Nr. 11 (18.11.2021): e1009546. http://dx.doi.org/10.1371/journal.pcbi.1009546.
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Construction of chromosomes 3D models based on single cell Hi-C data constitute an important challenge. We present a reconstruction approach, DPDchrom, that incorporates basic knowledge whether the reconstructed conformation should be coil-like or globular and spring relaxation at contact sites. In contrast to previously published protocols, DPDchrom can naturally form globular conformation due to the presence of explicit solvent. Benchmarking of this and several other methods on artificial polymer models reveals similar reconstruction accuracy at high contact density and DPDchrom advantage at low contact density. To compare 3D structures insensitively to spatial orientation and scale, we propose the Modified Jaccard Index. We analyzed two sources of the contact dropout: contact radius change and random contact sampling. We found that the reconstruction accuracy exponentially depends on the number of contacts per genomic bin allowing to estimate the reconstruction accuracy in advance. We applied DPDchrom to model chromosome configurations based on single-cell Hi-C data of mouse oocytes and found that these configurations differ significantly from a random one, that is consistent with other studies.
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Espelin, Christopher W., Kenneth B. Kaplan und Peter K. Sorger. „Probing the Architecture of a Simple Kinetochore Using DNA–Protein Crosslinking“. Journal of Cell Biology 139, Nr. 6 (15.12.1997): 1383–96. http://dx.doi.org/10.1083/jcb.139.6.1383.
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In budding yeast, accurate chromosome segregation requires that one and only one kinetochore assemble per chromosome. In this paper, we report the use of DNA–protein crosslinking and nondenaturing gel analysis to study the structure of CBF3, a four-protein complex that binds to the essential CDEIII region of Saccharomyces cerevisiae centromeres. We find that three subunits of CBF3 are in direct contact with CDEIII over a region of DNA that spans 80 bp. A highly asymmetric core complex containing p58CTF13 p64CEP3 and p110NDC10 in direct contact with DNA forms at the genetically defined center of CDEIII. This core complex spans ∼56 bp of CEN3. An extended complex comprising the core complex and additional DNA-bound p110NDC10 also forms. It spans ∼80 bp of DNA. CBF3 makes sequence-specific and -nonspecific contacts with DNA. Both contribute significantly to the energy of CBF3–DNA interaction. Moreover, important sequence-specific contacts are made with bases that are not conserved among yeast centromeres. These findings provide a foundation for understanding the organization of the CBF3–centromere complex, a structure that appears to initiate the formation of microtubule attachment sites at yeast kinetochores. These results also have implications for understanding centromere-binding proteins in higher cells.
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Tchurikov, Fedoseeva, Klushevskaya, Slovohotov, Chechetkin, Kravatsky und Kretova. „rDNA Clusters Make Contact with Genes that Are Involved in Differentiation and Cancer and Change Contacts after Heat Shock Treatment“. Cells 8, Nr. 11 (05.11.2019): 1393. http://dx.doi.org/10.3390/cells8111393.
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Human rDNA clusters form numerous contacts with different chromosomal regions as evidenced by chromosome conformation capture data. Heterochromatization of rDNA genes leads to heterochromatization in different chromosomal regions coupled with the activation of the transcription of genes related to differentiation. These data suggest a role for rDNA clusters in the regulation of many human genes. However, the genes that reside within the rDNA-contacting regions have not been identified. The purpose of this study was to detect and characterize the regions where rDNA clusters make frequent contacts and to identify and categorize genes located in these regions. We analyzed the regions that contact rDNA using 4C data and show that these regions are enriched with genes specifying transcription factors and non-coding RNAs involved in differentiation and development. The rDNA-contacting genes are involved in neuronal development and are associated with different cancers. Heat shock treatment led to dramatic changes in the pattern of rDNA-contacting sites, especially in the regions possessing long stretches of H3K27ac marks. Whole-genome analysis of rDNA-contacting sites revealed specific epigenetic marks and the transcription sites of 20–100 nt non-coding RNAs in these regions. The rDNA-contacting genes jointly regulate many genes that are involved in the control of transcription by RNA polymerase II and the development of neurons. Our data suggest a role for rDNA clusters in the differentiation of human cells and carcinogenesis.
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Nützmann, Hans-Wilhelm, Daniel Doerr, América Ramírez-Colmenero, Jesús Emiliano Sotelo-Fonseca, Eva Wegel, Marco Di Stefano, Steven W. Wingett et al. „Active and repressed biosynthetic gene clusters have spatially distinct chromosome states“. Proceedings of the National Academy of Sciences 117, Nr. 24 (03.06.2020): 13800–13809. http://dx.doi.org/10.1073/pnas.1920474117.
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While colocalization within a bacterial operon enables coexpression of the constituent genes, the mechanistic logic of clustering of nonhomologous monocistronic genes in eukaryotes is not immediately obvious. Biosynthetic gene clusters that encode pathways for specialized metabolites are an exception to the classical eukaryote rule of random gene location and provide paradigmatic exemplars with which to understand eukaryotic cluster dynamics and regulation. Here, using 3C, Hi-C, and Capture Hi-C (CHi-C) organ-specific chromosome conformation capture techniques along with high-resolution microscopy, we investigate how chromosome topology relates to transcriptional activity of clustered biosynthetic pathway genes inArabidopsis thaliana. Our analyses reveal that biosynthetic gene clusters are embedded in local hot spots of 3D contacts that segregate cluster regions from the surrounding chromosome environment. The spatial conformation of these cluster-associated domains differs between transcriptionally active and silenced clusters. We further show that silenced clusters associate with heterochromatic chromosomal domains toward the periphery of the nucleus, while transcriptionally active clusters relocate away from the nuclear periphery. Examination of chromosome structure at unrelated clusters in maize, rice, and tomato indicates that integration of clustered pathway genes into distinct topological domains is a common feature in plant genomes. Our results shed light on the potential mechanisms that constrain coexpression within clusters of nonhomologous eukaryotic genes and suggest that gene clustering in the one-dimensional chromosome is accompanied by compartmentalization of the 3D chromosome.
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Ren, Zhongqing, Constantin N. Takacs, Hugo B. Brandão, Christine Jacobs-Wagner und Xindan Wang. „Organization and replicon interactions within the highly segmented genome of Borrelia burgdorferi“. PLOS Genetics 19, Nr. 7 (26.07.2023): e1010857. http://dx.doi.org/10.1371/journal.pgen.1010857.
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Borrelia burgdorferi, a causative agent of Lyme disease, contains the most segmented bacterial genome known to date, with one linear chromosome and over twenty plasmids. How this unusually complex genome is organized, and whether and how the different replicons interact are unclear. We recently demonstrated that B. burgdorferi is polyploid and that the copies of the chromosome and plasmids are regularly spaced in each cell, which is critical for faithful segregation of the genome to daughter cells. Regular spacing of the chromosome is controlled by two separate partitioning systems that involve the protein pairs ParA/ParZ and ParB/Smc. Here, using chromosome conformation capture (Hi-C), we characterized the organization of the B. burgdorferi genome and the interactions between the replicons. We uncovered that although the linear chromosome lacks contacts between the two replication arms, the two telomeres are in frequent contact. Moreover, several plasmids specifically interact with the chromosome oriC region, and a subset of plasmids interact with each other more than with others. We found that Smc and the Smc-like MksB protein mediate long-range interactions on the chromosome, but they minimally affect plasmid-chromosome or plasmid-plasmid interactions. Finally, we found that disruption of the two partition systems leads to chromosome restructuring, correlating with the mis-positioning of chromosome oriC. Altogether, this study revealed the conformation of a complex genome and analyzed the contribution of the partition systems and SMC family proteins to this organization. This work expands the understanding of the organization and maintenance of multipartite bacterial genomes.
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Tan, Longzhi, Dong Xing, Chi-Han Chang, Heng Li und X. Sunney Xie. „Three-dimensional genome structures of single diploid human cells“. Science 361, Nr. 6405 (30.08.2018): 924–28. http://dx.doi.org/10.1126/science.aat5641.
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Three-dimensional genome structures play a key role in gene regulation and cell functions. Characterization of genome structures necessitates single-cell measurements. This has been achieved for haploid cells but has remained a challenge for diploid cells. We developed a single-cell chromatin conformation capture method, termed Dip-C, that combines a transposon-based whole-genome amplification method to detect many chromatin contacts, called META (multiplex end-tagging amplification), and an algorithm to impute the two chromosome haplotypes linked by each contact. We reconstructed the genome structures of single diploid human cells from a lymphoblastoid cell line and from primary blood cells with high spatial resolution, locating specific single-nucleotide and copy number variations in the nucleus. The two alleles of imprinted loci and the two X chromosomes were structurally different. Cells of different types displayed statistically distinct genome structures. Such structural cell typing is crucial for understanding cell functions.
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Gao, Yunfeng, Yong Hwee Foo, Ricksen S. Winardhi, Qingnan Tang, Jie Yan und Linda J. Kenney. „Charged residues in the H-NS linker drive DNA binding and gene silencing in single cells“. Proceedings of the National Academy of Sciences 114, Nr. 47 (06.11.2017): 12560–65. http://dx.doi.org/10.1073/pnas.1716721114.
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Nucleoid-associated proteins (NAPs) facilitate chromosome organization in bacteria, but the precise mechanism remains elusive. H-NS is a NAP that also plays a major role in silencing pathogen genes. We used genetics, single-particle tracking in live cells, superresolution microscopy, atomic force microscopy, and molecular dynamics simulations to examine H-NS/DNA interactions in single cells. We discovered a role for the unstructured linker region connecting the N-terminal oligomerization and C-terminal DNA binding domains. In the present work we demonstrate that linker amino acids promote engagement with DNA. In the absence of linker contacts, H-NS binding is significantly reduced, although no change in chromosome compaction is observed. H-NS is not localized to two distinct foci; rather, it is scattered all around the nucleoid. The linker makes DNA contacts that are required for gene silencing, while chromosome compaction does not appear to be an important H-NS function.
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Wolf, Klaus Werner. „Centromere structure and chromosome number in mitosis of the colourless phytoflagellate Polytoma papillatum (Chlorophyceae, Volvocales, Chlamydomonadaceae)“. Genome 38, Nr. 6 (01.12.1995): 1249–54. http://dx.doi.org/10.1139/g95-164.
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Centromere structure is described in mitosis of the unicellular biflagellate alga Polytoma papillatum using transmission electron microscopy. The kinetochores are five-layered elements at the poleward surface of the chromosomes. The five layers consist of three dense plates interspersed by two transparent zones. The polemost dense layer serves as the attachment site for kinetochore microtubules and the innermost dense layer is intimately associated with the chromatin. The five-layered organization of the kinetochore in the alga is unusual. In animals, three-layered kinetochores are the rule. This type has also been found in some algae, while higher plants do not possess striated kinetochores. An attempt was made to determine the chromosome number of P. papillatum. Individual chromosomes could not be recognized with confidence, since there were numerous lateral contacts between the chromosomes throughout mitosis. An alternative approach, however, was successful. Counting the kinetochores in serial sections through mitotic metaphase and anaphase plates revealed a number of 15 chromosomes.Key words: anaphase, kinetochore, metaphase, microtubule.
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Carstens, Simeon, Michael Nilges und Michael Habeck. „Bayesian inference of chromatin structure ensembles from population-averaged contact data“. Proceedings of the National Academy of Sciences 117, Nr. 14 (19.03.2020): 7824–30. http://dx.doi.org/10.1073/pnas.1910364117.
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Mounting experimental evidence suggests a role for the spatial organization of chromatin in crucial processes of the cell nucleus such as transcription regulation. Chromosome conformation capture techniques allow us to characterize chromatin structure by mapping contacts between chromosomal loci on a genome-wide scale. The most widespread modality is to measure contact frequencies averaged over a population of cells. Single-cell variants exist, but suffer from low contact numbers and have not yet gained the same resolution as population methods. While intriguing biological insights have already been garnered from ensemble-averaged data, information about three-dimensional (3D) genome organization in the underlying individual cells remains largely obscured because the contact maps show only an average over a huge population of cells. Moreover, computational methods for structure modeling of chromatin have mostly focused on fitting a single consensus structure, thereby ignoring any cell-to-cell variability in the model itself. Here, we propose a fully Bayesian method to infer ensembles of chromatin structures and to determine the optimal number of states in a principled, objective way. We illustrate our approach on simulated data and compute multistate models of chromatin from chromosome conformation capture carbon copy (5C) data. Comparison with independent data suggests that the inferred ensembles represent the underlying sample population faithfully. Harnessing the rich information contained in multistate models, we investigate cell-to-cell variability of chromatin organization into topologically associating domains, thus highlighting the ability of our approach to deliver insights into chromatin organization of great biological relevance.
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Belyaeva, E. S., L. V. Boldyreva, E. I. Volkova, R. A. Nanayev, A. A. Alekseyenko und I. F. Zhimulev. „Effect of the Suppressor of Underreplication (SuUR) Gene on Position-Effect Variegation Silencing in Drosophila melanogaster“. Genetics 165, Nr. 3 (01.11.2003): 1209–20. http://dx.doi.org/10.1093/genetics/165.3.1209.
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Abstract It has been previously shown that the SuUR gene encodes a protein located in intercalary and pericentromeric heterochromatin in Drosophila melanogaster polytene chromosomes. The SuUR mutation suppresses the formation of ectopic contacts and DNA underreplication in polytene chromosomes; SuUR+ in extra doses enhances the expression of these characters. This study demonstrates that heterochromatin-dependent PEV silencing is also influenced by SuUR. The SuUR protein localizes to chromosome regions compacted as a result of PEV; the SuUR mutation suppresses DNA underreplication arising in regions of polytene chromosomes undergoing PEV. The SuUR mutation also suppresses variegation of both adult morphological characters and chromatin compaction observed in rearranged chromosomes. In contrast, SuUR+ in extra doses and its overexpression enhance variegation. Thus, SuUR affects PEV silencing in a dose-dependent manner. However, its effect is expressed weaker than that of the strong modifier Su(var)2-5.
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Leung, Karen N., und Barbara Panning. „X-Inactivation: Xist RNA Uses Chromosome Contacts to Coat the X“. Current Biology 24, Nr. 2 (Januar 2014): R80—R82. http://dx.doi.org/10.1016/j.cub.2013.11.052.
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Fung, Jennifer C., Wallace F. Marshall, Abby Dernburg, David A. Agard und John W. Sedat. „Homologous Chromosome Pairing in Drosophila melanogaster Proceeds through Multiple Independent Initiations“. Journal of Cell Biology 141, Nr. 1 (06.04.1998): 5–20. http://dx.doi.org/10.1083/jcb.141.1.5.
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The dynamics by which homologous chromosomes pair is currently unknown. Here, we use fluorescence in situ hybridization in combination with three-dimensional optical microscopy to show that homologous pairing of the somatic chromosome arm 2L in Drosophila occurs by independent initiation of pairing at discrete loci rather than by a processive zippering of sites along the length of chromosome. By evaluating the pairing frequencies of 11 loci on chromosome arm 2L over several timepoints during Drosophila embryonic development, we show that all 11 loci are paired very early in Drosophila development, within 13 h after egg deposition. To elucidate whether such pairing occurs by directed or undirected motion, we analyzed the pairing kinetics of histone loci during nuclear cycle 14. By measuring changes of nuclear length and correlating these changes with progression of time during cycle 14, we were able to express the pairing frequency and distance between homologous loci as a function of time. Comparing the experimentally determined dynamics of pairing to simulations based on previously proposed models of pairing motion, we show that the observed pairing kinetics are most consistent with a constrained random walk model and not consistent with a directed motion model. Thus, we conclude that simple random contacts through diffusion could suffice to allow pairing of homologous sites.
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Kinney, Nicholas A., Igor V. Sharakhov und Alexey V. Onufriev. „A Model of Nuclear Organization Demonstrates the Effect of Nuclear Envelope - Chromosome Contacts on 3D Organization of Chromosomes“. Biophysical Journal 104, Nr. 2 (Januar 2013): 551a. http://dx.doi.org/10.1016/j.bpj.2012.11.3056.
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ROCHE, STEPHAN, und ENRIQUE MACIÁ. „ELECTRONIC TRANSPORT AND THERMOPOWER IN APERIODIC DNA SEQUENCES“. Modern Physics Letters B 18, Nr. 17 (30.07.2004): 847–71. http://dx.doi.org/10.1142/s021798490400744x.
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A detailed study of charge transport properties of synthetic and genomic DNA sequences is reported. Genomic sequences of the Chromosome 22, λ-bacteriophage, and D1s80 genes of Human and Pygmy chimpanzee are considered in this work, and compared with both periodic and quasiperiodic (Fibonacci) sequences of nucleotides. Charge transfer efficiency is compared for all these different sequences, and large variations in charge transfer efficiency, stemming from sequence-dependent effects, are reported. In addition, basic characteristics of tunneling currents, including contact effects, are described. Finally, the thermoelectric power of nucleobases connected in between metallic contacts at different temperatures is presented.
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Qian, Zhong, Victor B. Zhurkin und Sankar Adhya. „DNA–RNA interactions are critical for chromosome condensation inEscherichia coli“. Proceedings of the National Academy of Sciences 114, Nr. 46 (30.10.2017): 12225–30. http://dx.doi.org/10.1073/pnas.1711285114.
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Bacterial chromosome (nucleoid) conformation dictates faithful regulation of gene transcription. The conformation is condition-dependent and is guided by several nucleoid-associated proteins (NAPs) and at least one nucleoid-associated noncoding RNA, naRNA4. Here we investigated the molecular mechanism of how naRNA4 and the major NAP, HU, acting together organize the chromosome structure by establishing multiple DNA–DNA contacts (DNA condensation). We demonstrate that naRNA4 uniquely acts by forming complexes that may not involve long stretches of DNA–RNA hybrid. Also, uncommonly, HU, a chromosome-associated protein that is essential in the DNA–RNA interactions, is not present in the final complex. Thus, HU plays a catalytic (chaperone) role in the naRNA4-mediated DNA condensation process.
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Marshall, W. F., A. F. Dernburg, B. Harmon, D. A. Agard und J. W. Sedat. „Specific interactions of chromatin with the nuclear envelope: positional determination within the nucleus in Drosophila melanogaster.“ Molecular Biology of the Cell 7, Nr. 5 (Mai 1996): 825–42. http://dx.doi.org/10.1091/mbc.7.5.825.
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Specific interactions of chromatin with the nuclear envelope (NE) in early embryos of Drosophila melanogaster have been mapped and analyzed. Using fluorescence in situ hybridization, the three-dimensional positions of 42 DNA probes, primarily to chromosome 2L, have been mapped in nuclei of intact Drosophila embryos, revealing five euchromatic and two heterochromatic regions associated with the NE. These results predict that there are approximately 15 NE contacts per chromosome arm, which delimit large chromatin loops of approximately 1-2 Mb. These NE association sites do not strictly correlate with scaffold-attachment regions, heterochromatin, or binding sites of known chromatin proteins. Pairs of neighboring probes surrounding one NE association site were used to delimit the NE association site more precisely, suggesting that peripheral localization of a large stretch of chromatin is likely to result from NE association at a single discrete site. These NE interactions are not established until after telophase, by which time the nuclear envelope has reassembled around the chromosomes, and they are thus unlikely to be involved in binding of NE vesicles to chromosomes following mitosis. Analysis of positions of these probes also reveals that the interphase nucleus is strongly polarized in a Rabl configuration which, together with specific targeting to the NE or to the nuclear interior, results in each locus occupying a highly determined position within the nucleus.
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Lomov, Nikolai A., Vladimir S. Viushkov, Sergey V. Ulianov, Alexey A. Gavrilov, Daniil A. Alexeyevsky, Artem V. Artemov, Sergey V. Razin und Mikhail A. Rubtsov. „Recurrent Translocations in Topoisomerase Inhibitor-Related Leukemia Are Determined by the Features of DNA Breaks Rather Than by the Proximity of the Translocating Genes“. International Journal of Molecular Sciences 23, Nr. 17 (29.08.2022): 9824. http://dx.doi.org/10.3390/ijms23179824.
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Topoisomerase inhibitors are widely used in cancer chemotherapy. However, one of the potential long-term adverse effects of such therapy is acute leukemia. A key feature of such therapy-induced acute myeloid leukemia (t-AML) is recurrent chromosomal translocations involving AML1 (RUNX1) or MLL (KMT2A) genes. The formation of chromosomal translocation depends on the spatial proximity of translocation partners and the mobility of the DNA ends. It is unclear which of these two factors might be decisive for recurrent t-AML translocations. Here, we used fluorescence in situ hybridization (FISH) and chromosome conformation capture followed by sequencing (4C-seq) to investigate double-strand DNA break formation and the mobility of broken ends upon etoposide treatment, as well as contacts between translocation partner genes. We detected the separation of the parts of the broken AML1 gene, as well as the increased mobility of these separated parts. 4C-seq analysis showed no evident contacts of AML1 and MLL with loci, implicated in recurrent t-AML translocations, either before or after etoposide treatment. We suggest that separation of the break ends and their increased non-targeted mobility—but not spatial predisposition of the rearrangement partners—plays a major role in the formation of these translocations.
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Conte, Mattia, Andrea Esposito, Francesca Vercellone, Alex Abraham und Simona Bianco. „Unveiling the Machinery behind Chromosome Folding by Polymer Physics Modeling“. International Journal of Molecular Sciences 24, Nr. 4 (11.02.2023): 3660. http://dx.doi.org/10.3390/ijms24043660.
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Understanding the mechanisms underlying the complex 3D architecture of mammalian genomes poses, at a more fundamental level, the problem of how two or multiple genomic sites can establish physical contacts in the nucleus of the cells. Beyond stochastic and fleeting encounters related to the polymeric nature of chromatin, experiments have revealed specific, privileged patterns of interactions that suggest the existence of basic organizing principles of folding. In this review, we focus on two major and recently proposed physical processes of chromatin organization: loop-extrusion and polymer phase-separation, both supported by increasing experimental evidence. We discuss their implementation into polymer physics models, which we test against available single-cell super-resolution imaging data, showing that both mechanisms can cooperate to shape chromatin structure at the single-molecule level. Next, by exploiting the comprehension of the underlying molecular mechanisms, we illustrate how such polymer models can be used as powerful tools to make predictions in silico that can complement experiments in understanding genome folding. To this aim, we focus on recent key applications, such as the prediction of chromatin structure rearrangements upon disease-associated mutations and the identification of the putative chromatin organizing factors that orchestrate the specificity of DNA regulatory contacts genome-wide.
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Tanskanen, Antti O. „Intergenerational relations and child development in England“. Anthropological Review 80, Nr. 1 (01.03.2017): 127–39. http://dx.doi.org/10.1515/anre-2017-0007.
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Abstract Evolutionary studies have shown that in many traditional populations the beneficial effects of grandparental presence for grandchildren may vary according to the sex and lineage of the grandparents, as well as by the sex of the grandchild. However, few studies have investigated the relevance of these factors in modern developed societies. The present investigation uses the Millennium Cohort Study (n = 4,636 children) to analyse the association between grandparental investment and child development in contemporary England. Grandparental investment is measured by parent-grandparent contact frequencies at the child’s age of 3 and child development by “early learning goals” over the first year of primary school assessed with the Foundation Stage Profile (FSP). Children whose mothers reported contacts with maternal grandparents receive higher FSP scores compared to those with no contact at all. In addition, children whose fathers reported daily contacts with paternal grandfathers have lower FSP scores than other children. The study provides evidence of the relevance of grandparental investment on grandchild development also in developed societies. The results are discussed with reference to the grandmother hypothesis, sex-specific reproductive strategies and sex chromosome hypothesis.
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Zha, Mengsheng, Nan Wang, Chaoyang Zhang und Zheng Wang. „Inferring Single-Cell 3D Chromosomal Structures Based on the Lennard-Jones Potential“. International Journal of Molecular Sciences 22, Nr. 11 (31.05.2021): 5914. http://dx.doi.org/10.3390/ijms22115914.
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Reconstructing three-dimensional (3D) chromosomal structures based on single-cell Hi-C data is a challenging scientific problem due to the extreme sparseness of the single-cell Hi-C data. In this research, we used the Lennard-Jones potential to reconstruct both 500 kb and high-resolution 50 kb chromosomal structures based on single-cell Hi-C data. A chromosome was represented by a string of 500 kb or 50 kb DNA beads and put into a 3D cubic lattice for simulations. A 2D Gaussian function was used to impute the sparse single-cell Hi-C contact matrices. We designed a novel loss function based on the Lennard-Jones potential, in which the ε value, i.e., the well depth, was used to indicate how stable the binding of every pair of beads is. For the bead pairs that have single-cell Hi-C contacts and their neighboring bead pairs, the loss function assigns them stronger binding stability. The Metropolis–Hastings algorithm was used to try different locations for the DNA beads, and simulated annealing was used to optimize the loss function. We proved the correctness and validness of the reconstructed 3D structures by evaluating the models according to multiple criteria and comparing the models with 3D-FISH data.
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Hancock, Stephen P., Duilio Cascio und Reid C. Johnson. „Cooperative DNA binding by proteins through DNA shape complementarity“. Nucleic Acids Research 47, Nr. 16 (25.07.2019): 8874–87. http://dx.doi.org/10.1093/nar/gkz642.
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Abstract Localized arrays of proteins cooperatively assemble onto chromosomes to control DNA activity in many contexts. Binding cooperativity is often mediated by specific protein–protein interactions, but cooperativity through DNA structure is becoming increasingly recognized as an additional mechanism. During the site-specific DNA recombination reaction that excises phage λ from the chromosome, the bacterial DNA architectural protein Fis recruits multiple λ-encoded Xis proteins to the attR recombination site. Here, we report X-ray crystal structures of DNA complexes containing Fis + Xis, which show little, if any, contacts between the two proteins. Comparisons with structures of DNA complexes containing only Fis or Xis, together with mutant protein and DNA binding studies, support a mechanism for cooperative protein binding solely by DNA allostery. Fis binding both molds the minor groove to potentiate insertion of the Xis β-hairpin wing motif and bends the DNA to facilitate Xis-DNA contacts within the major groove. The Fis-structured minor groove shape that is optimized for Xis binding requires a precisely positioned pyrimidine-purine base-pair step, whose location has been shown to modulate minor groove widths in Fis-bound complexes to different DNA targets.
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Ingram, Samuel P., Nicholas T. Henthorn, John W. Warmenhoven, Norman F. Kirkby, Ranald I. Mackay, Karen J. Kirkby und Michael J. Merchant. „Hi-C implementation of genome structure for in silico models of radiation-induced DNA damage“. PLOS Computational Biology 16, Nr. 12 (16.12.2020): e1008476. http://dx.doi.org/10.1371/journal.pcbi.1008476.
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Developments in the genome organisation field has resulted in the recent methodology to infer spatial conformations of the genome directly from experimentally measured genome contacts (Hi-C data). This provides a detailed description of both intra- and inter-chromosomal arrangements. Chromosomal intermingling is an important driver for radiation-induced DNA mis-repair. Which is a key biological endpoint of relevance to the fields of cancer therapy (radiotherapy), public health (biodosimetry) and space travel. For the first time, we leverage these methods of inferring genome organisation and couple them to nano-dosimetric radiation track structure modelling to predict quantities and distribution of DNA damage within cell-type specific geometries. These nano-dosimetric simulations are highly dependent on geometry and are benefited from the inclusion of experimentally driven chromosome conformations. We show how the changes in Hi-C contract maps impact the inferred geometries resulting in significant differences in chromosomal intermingling. We demonstrate how these differences propagate through to significant changes in the distribution of DNA damage throughout the cell nucleus, suggesting implications for DNA repair fidelity and subsequent cell fate. We suggest that differences in the geometric clustering for the chromosomes between the cell-types are a plausible factor leading to changes in cellular radiosensitivity. Furthermore, we investigate changes in cell shape, such as flattening, and show that this greatly impacts the distribution of DNA damage. This should be considered when comparing in vitro results to in vivo systems. The effect may be especially important when attempting to translate radiosensitivity measurements at the experimental in vitro level to the patient or human level.
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Kim, Min Hyung, Yong Chan Kim, Heejung Kim, Hyuk Min Lee, Ju Hyun Lee, Da Ae Kim, Chanhee Kim, Jin Young Park und Yoon Soo Park. „Lessons Learned from an Experience with Vancomycin-Intermediate Staphylococcus aureus Outbreak in a Newly Built Secondary Hospital in Korea“. Pathogens 10, Nr. 5 (06.05.2021): 564. http://dx.doi.org/10.3390/pathogens10050564.
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A vancomycin-intermediate Staphylococcus aureus (VISA) outbreak occurred in an intensive care unit (ICU) in South Korea. We aimed to investigate the condition that led to the VISA outbreak and seek measures to prevent further spread of the multidrug-resistant organism. A total of three VISA isolates were obtained from two patients and a health care worker (HCW) in a newly built 450-bed secondary hospital. Extensive screening of close contacts for VISA in terms of space sharing and physical contact, irrespective of contact time, was performed. Furthermore, multilocus sequence type, staphylococcal cassette chromosome mec type, and spa type profiles were determined for all VISA isolates. The relationship between vancomycin use and the minimum inhibitory concentration (MIC) of S. aureus was also investigated. Molecular typing showed that the strains of the three VISA isolates were identical, indicating horizontal hospital transmission. We assumed that VISA colonised in the HCW could have transmitted to the two patients, which resulted in one infection and one colonisation. The affected HCW was excused from work and was decolonised with mupirocin. Five weeks after the interventions, no additional VISA isolates were identified. No relationship between vancomycin use and MIC of S. aureus was identified. Extensive screening of contacts in addition to decolonisation is crucial in preventing the further spread of VISA.
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Alexander, S. P., und C. L. Rieder. „Chromosome motion during attachment to the vertebrate spindle: initial saltatory-like behavior of chromosomes and quantitative analysis of force production by nascent kinetochore fibers.“ Journal of Cell Biology 113, Nr. 4 (15.05.1991): 805–15. http://dx.doi.org/10.1083/jcb.113.4.805.
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Before forming a monopolar attachment to the closest spindle pole, chromosomes attaching in newt (Taricha granulosa) pneumocytes generally reside in an optically clear region of cytoplasm that is largely devoid of cytoskeletal components, organelles, and other chromosomes. We have previously demonstrated that chromosome attachment in these cells occurs when an astral microtubule contacts one of the kinetochores (Hayden, J., S. S. Bowser, and C. L. Rieder. 1990. J. Cell Biol. 111:1039-1045), and that once this association is established the chromosome can be transported poleward along the surface of the microtubule (Rieder, C. L., and S. P. Alexander. 1990. J. Cell Biol. 110:81-95). In the study reported here we used video enhanced differential interference contrast light microscopy and digital image processing to compare, at high spatial and temporal resolution (0.1 microns and 0.93 s, respectively), the microtubule-mediated poleward movement of attaching chromosomes and poleward moving particles on the spindle. The results of this analysis demonstrate obvious similarities between minus end-directed particle motion on the newt pneumocyte spindle and the motion of attaching chromosomes. This is consistent with the hypothesis that both are driven by a similar force-generating mechanism. We then used the Brownian displacements of particles in the vicinity of attaching chromosomes to calculate the apparent viscosity of cytoplasm through which the chromosomes were moving. From these data, and that from our kinetic analyses and previous work, we calculate the force-producing potential of nascent kinetochore fibers in newt pneumocytes to be approximately 0.1-7.4 x 10(-6) dyn/microtubule) This is essentially equivalent to that calculated by Nicklas (Nicklas, R.B. 1988. Annu. Rev. Biophys. Biophys. Chem. 17:431-449) for prometaphase (4 x 10(-6) dyn/microtubule) and anaphase (5 x 10(-6) dyn/microtubule) chromosomes in Melanoplus. Thus, within the limits of experimental error, there appears to be a remarkable consistency in force production per microtubule throughout the various stages of mitosis and between groups of diverse taxonomic affinities.
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Yamamoto, Takaharu, Naozumi Harada, Kyoko Kano, Shin-ichiro Taya, Eli Canaani, Yoshiharu Matsuura, Akira Mizoguchi, Chizuka Ide und Kozo Kaibuchi. „The Ras Target AF-6 Interacts with ZO-1 and Serves as a Peripheral Component of Tight Junctions in Epithelial Cells“. Journal of Cell Biology 139, Nr. 3 (03.11.1997): 785–95. http://dx.doi.org/10.1083/jcb.139.3.785.
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The dynamic rearrangement of cell–cell junctions such as tight junctions and adherens junctions is a critical step in various cellular processes, including establishment of epithelial cell polarity and developmental patterning. Tight junctions are mediated by molecules such as occludin and its associated ZO-1 and ZO-2, and adherens junctions are mediated by adhesion molecules such as cadherin and its associated catenins. The transformation of epithelial cells by activated Ras results in the perturbation of cell–cell contacts. We previously identified the ALL-1 fusion partner from chromosome 6 (AF-6) as a Ras target. AF-6 has the PDZ domain, which is thought to localize AF-6 at the specialized sites of plasma membranes such as cell–cell contact sites. We investigated roles of Ras and AF-6 in the regulation of cell–cell contacts and found that AF-6 accumulated at the cell–cell contact sites of polarized MDCKII epithelial cells and had a distribution similar to that of ZO-1 but somewhat different from those of catenins. Immunoelectron microscopy revealed a close association between AF-6 and ZO-1 at the tight junctions of MDCKII cells. Native and recombinant AF-6 interacted with ZO-1 in vitro. ZO-1 interacted with the Ras-binding domain of AF-6, and this interaction was inhibited by activated Ras. AF-6 accumulated with ZO-1 at the cell–cell contact sites in cells lacking tight junctions such as Rat1 fibroblasts and PC12 rat pheochromocytoma cells. The overexpression of activated Ras in Rat1 cells resulted in the perturbation of cell–cell contacts, followed by a decrease of the accumulation of AF-6 and ZO-1 at the cell surface. These results indicate that AF-6 serves as one of the peripheral components of tight junctions in epithelial cells and cell–cell adhesions in nonepithelial cells, and that AF-6 may participate in the regulation of cell–cell contacts, including tight junctions, via direct interaction with ZO-1 downstream of Ras.
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Mizuguchi, Takeshi, Nitika Taneja, Emiko Matsuda, Jon-Matthew Belton, Peter FitzGerald, Job Dekker und Shiv I. S. Grewal. „Shelterin components mediate genome reorganization in response to replication stress“. Proceedings of the National Academy of Sciences 114, Nr. 21 (10.05.2017): 5479–84. http://dx.doi.org/10.1073/pnas.1705527114.
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The dynamic nature of genome organization impacts critical nuclear functions including the regulation of gene expression, replication, and DNA damage repair. Despite significant progress, the mechanisms responsible for reorganization of the genome in response to cellular stress, such as aberrant DNA replication, are poorly understood. Here, we show that fission yeast cells carrying a mutation in the DNA-binding protein Sap1 show defects in DNA replication progression and genome stability and display extensive changes in genome organization. Chromosomal regions such as subtelomeres that show defects in replication progression associate with the nuclear envelope in sap1 mutant cells. Moreover, high-resolution, genome-wide chromosome conformation capture (Hi-C) analysis revealed prominent contacts between telomeres and chromosomal arm regions containing replication origins proximal to binding sites for Taz1, a component of the Shelterin telomere protection complex. Strikingly, we find that Shelterin components are required for interactions between Taz1-associated chromosomal arm regions and telomeres. These analyses reveal an unexpected role for Shelterin components in genome reorganization in cells experiencing replication stress, with important implications for understanding the mechanisms governing replication and genome stability.
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Tchurikov, Nickolai A., Leonid A. Uroshlev, Elena S. Klushevskaya, Ildar R. Alembekov, Maria A. Lagarkova, Galina I. Kravatskaya, Vsevolod Y. Makeev und Yuri V. Kravatsky. „Chromosomal Translocations in NK-Cell Lymphomas Originate from Inter-Chromosomal Contacts of Active rDNA Clusters Possessing Hot Spots of DSBs“. Cancers 13, Nr. 15 (02.08.2021): 3889. http://dx.doi.org/10.3390/cancers13153889.
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Endogenous hot spots of DNA double-strand breaks (DSBs) are tightly linked with transcription patterns and cancer. There are nine hot spots of DSBs (denoted Pleiades) in human rDNA units that are located exclusively inside the intergenic spacer (IGS). Profiles of Pleiades coincide with the profiles of γ-H2AX, suggesting a high level of in vivo breakage inside rDNA genes. The data were confirmed by microscopic observation of the largest γ-H2AX foci inside nucleoli in interphase chromosomes. Circular chromosome conformation capture (4C) data indicate that the rDNA units often make contact with a specific set of chromosomal regions containing genes that are involved in differentiation and cancer. Interestingly, these regions also often possess hot spots of DSBs that provide the potential for Robertsonian and oncogenic translocations. In this study, we searched for translocations in which rDNA clusters are involved. The whole genome sequence (WGS) data of normal T cells and NK-cell lymphomas from the same individuals revealed numerous translocations in which Pleiades were involved. The sites of these translocations in normal T cells and in the lymphomas were mostly different, although there were also some common sites. The genes at translocations in normal cells and in lymphomas are associated with predominantly non-overlapping lists of genes that are depleted with silenced genes. Our data indicate that rDNA-mediated translocations occur at about the same frequency in the normal T cells and NK-lymphoma cells but differ at particular sites that correspond to open chromatin. We conclude that oncogenic translocations lead to dysregulation of a specific set of genes controlling development. In normal T cells and in NK cells, there are hot spots of translocations at sites possessing strong H3K27ac marks. The data indicate that Pleiades are involved in rDNA-mediated translocation.