The Experts below are selected from a list of 54648 Experts worldwide ranked by ideXlab platform
Prashant Bhat - One of the best experts on this subject based on the ideXlab platform.
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higher order inter chromosomal hubs shape 3d Genome Organization in the nucleus
2018Co-Authors: Sofia Quinodoz, Noah Ollikainen, Barbara Tabak, Ali Palla, Jan Marten Schmidt, Elizabeth Detmar, Mason Lai, Alexander A Shishkin, Prashant BhatAbstract:Eukaryotic Genomes are packaged into a 3-dimensional structure in the nucleus. Current methods for studying Genome-wide structure are based on proximity ligation. However, this approach can fail to detect known structures, such as interactions with nuclear bodies, because these DNA regions can be too far apart to directly ligate. Accordingly, our overall understanding of Genome Organization remains incomplete. Here, we develop split-pool recognition of interactions by tag extension (SPRITE), a method that enables Genome-wide detection of higher-order interactions within the nucleus. Using SPRITE, we recapitulate known structures identified by proximity ligation and identify additional interactions occurring across larger distances, including two hubs of inter-chromosomal interactions that are arranged around the nucleolus and nuclear speckles. We show that a substantial fraction of the Genome exhibits preferential Organization relative to these nuclear bodies. Our results generate a global model whereby nuclear bodies act as inter-chromosomal hubs that shape the overall packaging of DNA in the nucleus.
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higher order inter chromosomal hubs shape 3 dimensional Genome Organization in the nucleus
2017Co-Authors: Sofia Quinodoz, Noah Ollikainen, Barbara Tabak, Ali Palla, Jan Marten Schmidt, Elizabeth Detmar, Mason Lai, Alexander A Shishkin, Prashant Bhat, Vickie TrinhAbstract:Eukaryotic Genomes are packaged into a 3-dimensional structure in the nucleus of each cell. There are currently two distinct views of Genome Organization that are derived from different technologies. The first view, derived from Genome-wide proximity ligation methods (e.g. Hi-C), suggests that Genome Organization is largely organized around chromosomes. The second view, derived from in situ imaging, suggests a central role for nuclear bodies. Yet, because microscopy and proximity-ligation methods measure different aspects of Genome Organization, these two views remain poorly reconciled and our overall understanding of how genomic DNA is organized within the nucleus remains incomplete. Here, we develop Split-Pool Recognition of Interactions by Tag Extension (SPRITE), which moves away from proximity-ligation and enables Genome-wide detection of higher-order DNA interactions within the nucleus. Using SPRITE, we recapitulate known Genome structures identified by Hi-C and show that the contact frequencies measured by SPRITE strongly correlate with the 3-dimensional distances measured by microscopy. In addition to known structures, SPRITE identifies two major hubs of inter-chromosomal interactions that are spatially arranged around the nucleolus and nuclear speckles, respectively. We find that the majority of genomic regions exhibit preferential spatial association relative to one of these nuclear bodies, with regions that are highly transcribed by RNA Polymerase II organizing around nuclear speckles and transcriptionally inactive and centromere-proximal regions organizing around the nucleolus. Together, our results reconcile the two distinct pictures of nuclear structure and demonstrate that nuclear bodies act as inter-chromosomal hubs that shape the overall 3-dimensional packaging of genomic DNA in the nucleus.
Bin Zhang - One of the best experts on this subject based on the ideXlab platform.
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data driven polymer model for mechanistic exploration of diploid Genome Organization
2020Co-Authors: Alejandro Reyes, Sarah E Johnstone, Martin J Aryee, Bradley E Bernstein, Bin ZhangAbstract:Chromosomes are positioned nonrandomly inside the nucleus to coordinate with their transcriptional activity. The molecular mechanisms that dictate the global Genome Organization and the nuclear localization of individual chromosomes are not fully understood. We introduce a polymer model to study the Organization of the diploid human Genome. It is data-driven because all parameters can be derived from Hi-C data; it is also a mechanistic model because the energy function is explicitly written out based on a few biologically motivated hypotheses. These two features distinguish the model from existing approaches and make it useful both for reconstructing Genome structures and for exploring the principles of Genome Organization. We carried out extensive validations to show that simulated Genome structures reproduce a wide variety of experimental measurements, including chromosome radial positions and spatial distances between homologous pairs. Detailed mechanistic investigations support the importance of both specific interchromosomal interactions and centromere clustering for chromosome positioning. We anticipate the polymer model, when combined with Hi-C experiments, to be a powerful tool for investigating large-scale rearrangements in Genome structure upon cell differentiation and tumor progression.
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data driven polymer model for mechanistic exploration of diploid Genome Organization
2020Co-Authors: Alejandro Reyes, Sarah E Johnstone, Martin J Aryee, Bradley E Bernstein, Bin ZhangAbstract:Abstract Chromosomes are positioned non-randomly inside the nucleus to coordinate with their transcriptional activity. The molecular mechanisms that dictate the global Genome Organization and the nuclear localization of individual chromosomes are not fully understood. We introduce a polymer model to study the Organization of the diploid human Genome: it is data-driven as all parameters can be derived from Hi-C data; it is also a mechanistic model since the energy function is explicitly written out based on a few biologically motivated hypotheses. These two features distinguish the model from existing approaches and make it useful both for reconstructing Genome structures and for exploring the principles of Genome Organization. We carried out extensive validations to show that simulated Genome structures reproduce a wide variety of experimental measurements, including chromosome radial positions and spatial distances between homologous pairs. Detailed mechanistic investigations support the importance of both specific inter-chromosomal interactions and centromere clustering for chromosome positioning. We anticipate the polymer model, when combined with Hi-C experiments, to be a powerful tool for investigating large scale rearrangements in Genome structure upon cell differentiation and tumor progression.
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predicting three dimensional Genome Organization with chromatin states
2019Co-Authors: Bin ZhangAbstract:We introduce a computational model to simulate chromatin structure and dynamics. Starting from one-dimensional genomics and epigenomics data that are available for hundreds of cell types, this model enables de novo prediction of chromatin structures at five-kilo-base resolution. Simulated chromatin structures recapitulate known features of Genome Organization, including the formation of chromatin loops, topologically associating domains (TADs) and compartments, and are in quantitative agreement with chromosome conformation capture experiments and super-resolution microscopy measurements. Detailed characterization of the predicted structural ensemble reveals the dynamical flexibility of chromatin loops and the presence of cross-talk among neighboring TADs. Analysis of the model’s energy function uncovers distinct mechanisms for chromatin folding at various length scales and suggests a need to go beyond simple A/B compartment types to predict specific contacts between regulatory elements using polymer simulations.
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predicting three dimensional Genome Organization with chromatin states
2018Co-Authors: Bin ZhangAbstract:We introduce a computational model to simulate chromatin structure and dynamics. Starting from one-dimensional genomics and epigenomics data that are available for hundreds of cell types, this model enables de novo prediction of chromatin structures at five-kilo-base resolution. Simulated chromatin structures recapitulate known features of Genome Organization, including the formation of chromatin loops, topologically associating domains (TADs) and compartments, and are in quantitative agreements with chromosome conformation capture experiments and super-resolution microscopy measurements. Detailed characterization of the predicted structural ensemble reveals the dynamical flexibility of chromatin loops and the presence of cross-talks among neighboring TADs. Analysis of the model9s energy function uncovers the presence of distinct mechanisms for chromatin folding at various length scales.
Sofia Quinodoz - One of the best experts on this subject based on the ideXlab platform.
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higher order inter chromosomal hubs shape 3d Genome Organization in the nucleus
2018Co-Authors: Sofia Quinodoz, Noah Ollikainen, Barbara Tabak, Ali Palla, Jan Marten Schmidt, Elizabeth Detmar, Mason Lai, Alexander A Shishkin, Prashant BhatAbstract:Eukaryotic Genomes are packaged into a 3-dimensional structure in the nucleus. Current methods for studying Genome-wide structure are based on proximity ligation. However, this approach can fail to detect known structures, such as interactions with nuclear bodies, because these DNA regions can be too far apart to directly ligate. Accordingly, our overall understanding of Genome Organization remains incomplete. Here, we develop split-pool recognition of interactions by tag extension (SPRITE), a method that enables Genome-wide detection of higher-order interactions within the nucleus. Using SPRITE, we recapitulate known structures identified by proximity ligation and identify additional interactions occurring across larger distances, including two hubs of inter-chromosomal interactions that are arranged around the nucleolus and nuclear speckles. We show that a substantial fraction of the Genome exhibits preferential Organization relative to these nuclear bodies. Our results generate a global model whereby nuclear bodies act as inter-chromosomal hubs that shape the overall packaging of DNA in the nucleus.
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higher order inter chromosomal hubs shape 3 dimensional Genome Organization in the nucleus
2017Co-Authors: Sofia Quinodoz, Noah Ollikainen, Barbara Tabak, Ali Palla, Jan Marten Schmidt, Elizabeth Detmar, Mason Lai, Alexander A Shishkin, Prashant Bhat, Vickie TrinhAbstract:Eukaryotic Genomes are packaged into a 3-dimensional structure in the nucleus of each cell. There are currently two distinct views of Genome Organization that are derived from different technologies. The first view, derived from Genome-wide proximity ligation methods (e.g. Hi-C), suggests that Genome Organization is largely organized around chromosomes. The second view, derived from in situ imaging, suggests a central role for nuclear bodies. Yet, because microscopy and proximity-ligation methods measure different aspects of Genome Organization, these two views remain poorly reconciled and our overall understanding of how genomic DNA is organized within the nucleus remains incomplete. Here, we develop Split-Pool Recognition of Interactions by Tag Extension (SPRITE), which moves away from proximity-ligation and enables Genome-wide detection of higher-order DNA interactions within the nucleus. Using SPRITE, we recapitulate known Genome structures identified by Hi-C and show that the contact frequencies measured by SPRITE strongly correlate with the 3-dimensional distances measured by microscopy. In addition to known structures, SPRITE identifies two major hubs of inter-chromosomal interactions that are spatially arranged around the nucleolus and nuclear speckles, respectively. We find that the majority of genomic regions exhibit preferential spatial association relative to one of these nuclear bodies, with regions that are highly transcribed by RNA Polymerase II organizing around nuclear speckles and transcriptionally inactive and centromere-proximal regions organizing around the nucleolus. Together, our results reconcile the two distinct pictures of nuclear structure and demonstrate that nuclear bodies act as inter-chromosomal hubs that shape the overall 3-dimensional packaging of genomic DNA in the nucleus.
Liselotte Sundström - One of the best experts on this subject based on the ideXlab platform.
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Genome Organization and molecular characterization of the three Formica exsecta viruses-FeV1, FeV2 and FeV4.
2019Co-Authors: Kishor Dhaygude, Helena Johansson, Jonna Kulmuni, Liselotte SundströmAbstract:We present the Genome Organization and molecular characterization of the three Formica exsecta viruses, along with ORF predictions, and functional annotation of genes. The Formica exsecta virus-4 (FeV4; GenBank ID: {"type":"entrez-nucleotide","attrs":{"text":"MF287670","term_id":"1444544064","term_text":"MF287670"}}MF287670) is a newly discovered negative-sense single-stranded RNA virus representing the first identified member of order Mononegavirales in ants, whereas the Formica exsecta virus-1 (FeV1; GenBank ID: {"type":"entrez-nucleotide","attrs":{"text":"KF500001","term_id":"563616038","term_text":"KF500001"}}KF500001), and the Formica exsecta virus-2 (FeV2; GenBank ID: {"type":"entrez-nucleotide","attrs":{"text":"KF500002","term_id":"563616050","term_text":"KF500002"}}KF500002) are positive single-stranded RNA viruses initially identified (but not characterized) in our earlier study. The new virus FeV4 was found by re-analyzing data from a study published earlier. The Formica exsecta virus-4 Genome is 9,866 bp in size, with an overall G + C content of 44.92%, and containing five predicted open reading frames (ORFs). Our bioinformatics analysis indicates that gaps are absent and the ORFs are complete, which based on our comparative genomics analysis suggests that the Genomes are complete. Following the characterization, we validate virus infection for FeV1, FeV2 and FeV4 for the first time in field-collected worker ants. Some colonies were infected by multiple viruses, and the viruses were observed to infect all castes, and multiple life stages of workers and queens. Finally, highly similar viruses were expressed in adult workers and queens of six other Formica species: F. fusca, F. pressilabris, F. pratensis, F. aquilonia, F. truncorum and F. cinerea. This research indicates that viruses can be shared between ant species, but further studies on viral transmission are needed to understand viral infection pathways.
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Genome Organization and molecular characterization of the three Formica exsecta viruses—FeV1, FeV2 and FeV4
2019Co-Authors: Kishor Dhaygude, Helena Johansson, Jonna Kulmuni, Liselotte SundströmAbstract:We present the Genome Organization and molecular characterization of the three Formica exsecta viruses, along with ORF predictions, and functional annotation of genes. The Formica exsecta virus-4 (FeV4; GenBank ID: MF287670) is a newly discovered negative-sense single-stranded RNA virus representing the first identified member of order Mononegavirales in ants, whereas the Formica exsecta virus-1 (FeV1; GenBank ID: KF500001), and the Formica exsecta virus-2 (FeV2; GenBank ID: KF500002) are positive single-stranded RNA viruses initially identified (but not characterized) in our earlier study. The new virus FeV4 was found by re-analyzing data from a study published earlier. The Formica exsecta virus-4 Genome is 9,866 bp in size, with an overall G + C content of 44.92%, and containing five predicted open reading frames (ORFs). Our bioinformatics analysis indicates that gaps are absent and the ORFs are complete, which based on our comparative genomics analysis suggests that the Genomes are complete. Following the characterization, we validate virus infection for FeV1, FeV2 and FeV4 for the first time in field-collected worker ants. Some colonies were infected by multiple viruses, and the viruses were observed to infect all castes, and multiple life stages of workers and queens. Finally, highly similar viruses were expressed in adult workers and queens of six other Formica species: F. fusca, F. pressilabris, F. pratensis, F. aquilonia, F. truncorum and F. cinerea. This research indicates that viruses can be shared between ant species, but further studies on viral transmission are needed to understand viral infection pathways
Tom Misteli - One of the best experts on this subject based on the ideXlab platform.
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molecular basis and biological function of variability in spatial Genome Organization
2019Co-Authors: Elizabeth H Finn, Tom MisteliAbstract:The complex three-dimensional Organization of Genomes in the cell nucleus arises from a wide range of architectural features including DNA loops, chromatin domains, and higher-order compartments. Although these features are universally present in most cell types and tissues, recent single-cell biochemistry and imaging approaches have demonstrated stochasticity in transcription and high variability of chromatin architecture in individual cells. We review the occurrence, mechanistic basis, and functional implications of stochasticity in Genome Organization. We summarize recent observations on cell- and allele-specific variability of Genome architecture, discuss the nature of extrinsic and intrinsic sources of variability in Genome Organization, and highlight potential implications of structural heterogeneity for Genome function.
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extensive heterogeneity and intrinsic variation in spatial Genome Organization
2019Co-Authors: Elizabeth H Finn, Gianluca Pegoraro, Hugo B Brandao, Annelaure Valton, Marlies E Oomen, Job Dekker, Leonid A Mirny, Tom MisteliAbstract:Several general principles of global 3D Genome Organization have recently been established, including non-random positioning of chromosomes and genes in the cell nucleus, distinct chromatin compartments, and topologically associating domains (TADs). However, the extent and nature of cell-to-cell and cell-intrinsic variability in Genome architecture are still poorly characterized. Here, we systematically probe heterogeneity in Genome Organization. High-throughput optical mapping of several hundred intra-chromosomal interactions in individual human fibroblasts demonstrates low association frequencies, which are determined by genomic distance, higher-order chromatin architecture, and chromatin environment. The structure of TADs is variable between individual cells, and inter-TAD associations are common. Furthermore, single-cell analysis reveals independent behavior of individual alleles in single nuclei. Our observations reveal extensive variability and heterogeneity in Genome Organization at the level of individual alleles and demonstrate the coexistence of a broad spectrum of Genome configurations in a cell population.
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higher order Genome Organization in human disease
2010Co-Authors: Tom MisteliAbstract:Genomes are organized into complex higher-order structures by folding of the DNA into chromatin fibers, chromosome domains, and ultimately chromosomes. The higher-order Organization of Genomes is functionally important for gene regulation and control of gene expression programs. Defects in how chromatin is globally organized are relevant for physiological and pathological processes. Mutations and transcriptional misregulation of several global Genome organizers are linked to human diseases and global alterations in chromatin structure are emerging as key players in maintenance of Genome stability, aging, and the formation of cancer translocations.
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Spatial Genome Organization in the formation of chromosomal translocations
2006Co-Authors: Karen J. Meaburn, Tom Misteli, Evi SoutoglouAbstract:Chromosomal translocations and genomic instability are universal hallmarks of tumor cells. While the molecular mechanisms leading to the formation of translocations are rapidly being elucidated, a cell biological understanding of how chromosomes undergo translocations in the context of the cell nucleus in vivo is largely lacking. The recent realization that Genomes are non-randomly arranged within the nuclear space has profound consequences for mechanisms of chromosome translocations. We review here the emerging principles of spatial Genome Organization and discuss the implications of non-random spatial Genome Organization for the genesis and specificity of cancerous chromosomal translocations.