scholarly journals Chromosomal Rearrangements and Altered Nuclear Organization: Recent Mechanistic Models in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5860
Author(s):  
Concetta Federico ◽  
Francesca Bruno ◽  
Denise Ragusa ◽  
Craig S. Clements ◽  
Desiree Brancato ◽  
...  
Keyword(s):  
Genome Organization ◽  
Chromosomal Rearrangements ◽  
Nuclear Architecture ◽  
Interphase Nuclei ◽  
Individual Gene ◽  
New Information ◽  
Gene Positioning ◽  
Topologically Associated Domains ◽  
Health And Disease ◽  
Spatial Positioning

The last decade has seen significant progress in understanding how the genome is organized spatially within interphase nuclei. Recent analyses have confirmed earlier molecular cytogenetic studies on chromosome positioning within interphase nuclei and provided new information about the topologically associated domains (TADs). Examining the nuances of how genomes are organized within interphase nuclei will provide information fundamental to understanding gene regulation and expression in health and disease. Indeed, the radial spatial positioning of individual gene loci within nuclei has been associated with up- and down-regulation of specific genes, and disruption of normal genome organization within nuclei will result in compromised cellular health. In cancer cells, where reorganization of the nuclear architecture may occur in the presence of chromosomal rearrangements such as translocations, inversions, or deletions, gene repositioning can change their expression. To date, very few studies have focused on radial gene positioning and the correlation to gene expression in cancers. Further investigations would improve our understanding of the biological mechanisms at the basis of cancer and, in particular, in leukemia initiation and progression, especially in those cases where the molecular consequences of chromosomal rearrangements are still unclear. In this review, we summarize the main milestones in the field of genome organization in the nucleus and the alterations to this organization that can lead to cancer diseases.

scholarly journals Assessment of the Utility of Gene Positioning Biomarkers in the Stratification of Prostate Cancers

2019 ◽  
Author(s):  
Karen J. Meaburn ◽  
Tom Misteli
Keyword(s):  
Genome Organization ◽  
Metastatic Cancer ◽  
Cell Types ◽  
Specific Gene ◽  
Gene Positioning ◽  
Spatial Reorganization ◽  
Prostate Cancers ◽  
Spatial Positioning ◽  
Context Specific ◽  
Spatial Genome Organization

AbstractIn eukaryotic cells, the genome is spatially organized in a non-random fashion within the confines of the interphase nucleus, and most genes occupy preferred nuclear positions. For some genomic loci these positioning patterns are context specific, reflected in the distinct location of certain genes and chromosomes in different cell types and in disease. Disease-related differential spatial positioning of genes has led to the hypothesis that the spatial reorganization of the genome may be utilized as a diagnostic biomarker. In keeping with this possibility, the positioning patterns of specific genes can be used to reproducibly discriminate benign tissues from cancerous ones. In addition to the use of spatial genome organization for diagnostic purposes, we explore here the potential use of spatial genome organization as a prognostic tool. This is a pressing need since in many cancer types there is a lack of accurate markers to predict the aggressiveness of individual tumors. We find that directional repositioning of SP100 and TGFB3 gene loci stratifies prostate cancers of differing Gleason scores. A more peripheral position of SP100 and TGFB3 in the nucleus, compared to benign tissues, is associated with low Gleason score cancers, whereas more internal positioning correlates with higher Gleason scores. Conversely, LMNA is more internally positioned in many non-metastatic prostate cancers, while its position is indistinguishable from benign tissue in metastatic cancer. Our findings of subtype-specific gene positioning patterns in prostate cancer provides a proof-of-concept for the potential usefulness of spatial gene positioning as a prognostic biomarker.

Exploring the relationship between interphase gene positioning, transcriptional regulation and the nuclear matrix

2010 ◽  
Vol 38 (1) ◽  
pp. 263-267 ◽  
Author(s):  
Lauren S. Elcock ◽  
Joanna M. Bridger
Keyword(s):  
Nuclear Matrix ◽  
Local Scale ◽  
Proliferating Cells ◽  
Interphase Nuclei ◽  
Gene Positioning ◽  
Global Organization ◽  
Spatial Positioning ◽  
The Relationship

Since the advent of FISH (fluorescence in situ hybridization), there have been major advances in our understanding of how the genome is organized in interphase nuclei. Indeed, this organization is found to be non-random and individual chromosomes occupy discrete regions known as territories. Determining the factors that drive the spatial positioning of these territories within nuclei has caused much debate; however, in proliferating cells, there is evidently a correlation between radial positioning and gene density. Indeed, gene-poor chromosomes tend to be located towards the nuclear edge, while those that are more gene-rich are positioned more internally. These observations pose a number of questions: first, what is the function of this global organization and, secondly, is it representative of that occurring at a more local scale? During the course of this review, these questions will be considered, in light of the current literature regarding the role of transcription factories and the nuclear matrix in interphase genome organization.

scholarly journals Nuclear Envelope Integrity in Health and Disease: Consequences on Genome Instability and Inflammation

2021 ◽  
Vol 22 (14) ◽  
pp. 7281
Author(s):  
Benoit R. Gauthier ◽  
Valentine Comaills
Keyword(s):  
Nuclear Envelope ◽  
Clinical Symptoms ◽  
Genome Instability ◽  
Chromosomal Rearrangements ◽  
Wide Range ◽  
Complex Chromosomal Rearrangements ◽  
Health And Disease ◽  
Dna Release ◽  
Sting Pathway ◽  
Eukaryote Genome

The dynamic nature of the nuclear envelope (NE) is often underestimated. The NE protects, regulates, and organizes the eukaryote genome and adapts to epigenetic changes and to its environment. The NE morphology is characterized by a wide range of diversity and abnormality such as invagination and blebbing, and it is a diagnostic factor for pathologies such as cancer. Recently, the micronuclei, a small nucleus that contains a full chromosome or a fragment thereof, has gained much attention. The NE of micronuclei is prone to collapse, leading to DNA release into the cytoplasm with consequences ranging from the activation of the cGAS/STING pathway, an innate immune response, to the creation of chromosomal instability. The discovery of those mechanisms has revolutionized the understanding of some inflammation-related diseases and the origin of complex chromosomal rearrangements, as observed during the initiation of tumorigenesis. Herein, we will highlight the complexity of the NE biology and discuss the clinical symptoms observed in NE-related diseases. The interplay between innate immunity, genomic instability, and nuclear envelope leakage could be a major focus in future years to explain a wide range of diseases and could lead to new classes of therapeutics.

scholarly journals LncRNA:DNA triplex-forming sites are positioned at specific areas of genome organization and are predictors for Topologically Associated Domains

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Benjamin Soibam ◽  
Ayzhamal Zhamangaraeva
Keyword(s):  
Genome Organization ◽  
Chromatin Organization ◽  
Ctcf Binding ◽  
General Mechanism ◽  
Promoter Regions ◽  
Cellular Processes ◽  
A Genome ◽  
Topologically Associated Domains ◽  
Multiple Cell ◽  
Genomic Regions

Abstract Background Chromosomes are organized into units called topologically associated domains (TADs). TADs dictate regulatory landscapes and other DNA-dependent processes. Even though various factors that contribute to the specification of TADs have been proposed, the mechanism is not fully understood. Understanding the process for specification and maintenance of these units is essential in dissecting cellular processes and disease mechanisms. Results In this study, we report a genome-wide study that considers the idea of long noncoding RNAs (lncRNAs) mediating chromatin organization using lncRNA:DNA triplex-forming sites (TFSs). By analyzing the TFSs of expressed lncRNAs in multiple cell lines, we find that they are enriched in TADs, their boundaries, and loop anchors. However, they are evenly distributed across different regions of a TAD showing no preference for any specific portions within TADs. No relationship is observed between the locations of these TFSs and CTCF binding sites. However, TFSs are located not just in promoter regions but also in intronic, intergenic, and 3’UTR regions. We also show these triplex-forming sites can be used as predictors in machine learning models to discriminate TADs from other genomic regions. Finally, we compile a list of important “TAD-lncRNAs” which are top predictors for TADs identification. Conclusions Our observations advocate the idea that lncRNA:DNA TFSs are positioned at specific areas of the genome organization and are important predictors for TADs. LncRNA:DNA triplex formation most likely is a general mechanism of action exhibited by some lncRNAs, not just for direct gene regulation but also to mediate 3D chromatin organization.

Chromosomes exhibit preferential positioning in nuclei of quiescent human cells

1999 ◽  
Vol 112 (4) ◽  
pp. 525-535 ◽  
Author(s):  
R.G. Nagele ◽  
T. Freeman ◽  
L. McMorrow ◽  
Z. Thomson ◽  
K. Kitson-Wind ◽  
...  
Keyword(s):  
Human Fibroblasts ◽  
Dna Probes ◽  
Human Cells ◽  
Reference Points ◽  
Chromosome X ◽  
Interphase Nuclei ◽  
Interphase Chromosome ◽  
Chromosome Topology ◽  
Spatial Positioning ◽  
Diploid Cells

The relative spatial positioning of chromosomes 7, 8, 16, X and Y was examined in nuclei of quiescent (noncycling) diploid and triploid human fibroblasts using fluorescence in situ hybridization (FISH) with chromosome-specific DNA probes and digital imaging. In quiescent diploid cells, interhomolog distances and chromosome homolog position maps revealed a nonrandom, preferential topology for chromosomes 7, 8 and 16, whereas chromosome X approximated a more random distribution. Variations in the orientation of nuclei on the culture substratum tended to hinder detection of an ordered chromosome topology at interphase by biasing homolog position maps towards random distributions. Using two chromosome X homologs as reference points in triploid cells (karyotype = 69, XXY), the intranuclear location of chromosome Y was found to be predictable within remarkably narrow spatial limits. Dual-FISH with various combinations of chromosome-specific DNA probes and contrasting fluorochromes was used to identify adjacent chromosomes in mitotic rosettes and test whether they are similarly positioned in interphase nuclei. From among the combinations tested, chromosomes 8 and 11 were found to be closely apposed in most mitotic rosettes and interphase nuclei. Overall, results suggest the existence of an ordered interphase chromosome topology in quiescent human cells in which at least some chromosome homologs exhibit a preferred relative intranuclear location that may correspond to the observed spatial order of chromosomes in rosettes of mitotic cells.

scholarly journals Genome organization via loop extrusion, insights from polymer physics models

2019 ◽  
Vol 19 (2) ◽  
pp. 119-127 ◽  
Author(s):  
Surya K Ghosh ◽  
Daniel Jost
Keyword(s):  
Genome Organization ◽  
Extrusion Process ◽  
Polymer Physics ◽  
Modern Biology ◽  
Precise Information ◽  
Multi Scale ◽  
Topologically Associated Domains ◽  
Structural Maintenance Of Chromosome ◽  
Smc Proteins

Abstract Understanding how genomes fold and organize is one of the main challenges in modern biology. Recent high-throughput techniques like Hi-C, in combination with cutting-edge polymer physics models, have provided access to precise information on 3D chromosome folding to decipher the mechanisms driving such multi-scale organization. In particular, structural maintenance of chromosome (SMC) proteins play an important role in the local structuration of chromatin, putatively via a loop extrusion process. Here, we review the different polymer physics models that investigate the role of SMCs in the formation of topologically associated domains (TADs) during interphase via the formation of dynamic loops. We describe the main physical ingredients, compare them and discuss their relevance against experimental observations.

scholarly journals A Balance Between Intermediate Filaments and Microtubules Maintains Nuclear Architecture in the Cardiomyocyte

2020 ◽  
Vol 126 (3) ◽  
Author(s):  
Julie Heffler ◽  
Parisha P. Shah ◽  
Patrick Robison ◽  
Sai Phyo ◽  
Kimberly Veliz ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Intermediate Filaments ◽  
Genome Organization ◽  
Contractile Function ◽  
Nuclear Architecture ◽  
Super Resolution ◽  
Nuclear Lamina ◽  
Linc Complex ◽  
Spectrin Repeat ◽  
Balance Of Forces

Rationale: Mechanical forces are transduced to nuclear responses via the linkers of the nucleoskeleton and cytoskeleton (LINC) complex, which couples the cytoskeleton to the nuclear lamina and associated chromatin. While disruption of the LINC complex can cause cardiomyopathy, the relevant interactions that bridge the nucleoskeleton to cytoskeleton are poorly understood in the cardiomyocyte, where cytoskeletal organization is unique. Furthermore, while microtubules and desmin intermediate filaments associate closely with cardiomyocyte nuclei, the importance of these interactions is unknown. Objective: Here, we sought to determine how cytoskeletal interactions with the LINC complex regulate nuclear homeostasis in the cardiomyocyte. Methods and Results: To this end, we acutely disrupted the LINC complex, microtubules, actin, and intermediate filaments and assessed the consequences on nuclear morphology and genome organization in rat ventricular cardiomyocytes via a combination of super-resolution imaging, biophysical, and genomic approaches. We find that a balance of dynamic microtubules and desmin intermediate filaments is required to maintain nuclear shape and the fidelity of the nuclear envelope and lamina. Upon depletion of desmin (or nesprin [nuclear envelope spectrin repeat protein]-3, its binding partner in the LINC complex), polymerizing microtubules collapse the nucleus and drive infolding of the nuclear membrane. This results in DNA damage, a loss of genome organization, and broad transcriptional changes. The collapse in nuclear integrity is concomitant with compromised contractile function and may contribute to the pathophysiological changes observed in desmin-related myopathies. Conclusions: Disrupting the tethering of desmin to the nucleus results in a loss of nuclear homeostasis and rapid alterations to cardiomyocyte function. Our data suggest that a balance of forces imposed by intermediate filaments and microtubules is required to maintain nuclear structure and genome organization in the cardiomyocyte.

scholarly journals Topologically associated domains enriched for lineage-specific genes reveal expression-dependent nuclear topologies during myogenesis

2016 ◽  
Vol 113 (12) ◽  
pp. E1691-E1700 ◽  
Author(s):  
Daniel S. Neems ◽  
Arturo G. Garza-Gongora ◽  
Erica D. Smith ◽  
Steven T. Kosak
Keyword(s):  
Gene Regulation ◽  
Genome Organization ◽  
Spatial Organization ◽  
Potential Role ◽  
Spatial Distance ◽  
Linear Distribution ◽  
Myotube Formation ◽  
Topologically Associated Domains ◽  
The Relationship ◽  
Lineage Specific Genes

The linear distribution of genes across chromosomes and the spatial localization of genes within the nucleus are related to their transcriptional regulation. The mechanistic consequences of linear gene order, and how it may relate to the functional output of genome organization, remain to be fully resolved, however. Here we tested the relationship between linear and 3D organization of gene regulation during myogenesis. Our analysis has identified a subset of topologically associated domains (TADs) that are significantly enriched for muscle-specific genes. These lineage-enriched TADs demonstrate an expression-dependent pattern of nuclear organization that influences the positioning of adjacent nonenriched TADs. Therefore, lineage-enriched TADs inform cell-specific genome organization during myogenesis. The reduction of allelic spatial distance of one of these domains, which contains Myogenin, correlates with reduced transcriptional variability, identifying a potential role for lineage-specific nuclear topology. Using a fusion-based strategy to decouple mitosis and myotube formation, we demonstrate that the cell-specific topology of syncytial nuclei is dependent on cell division. We propose that the effects of linear and spatial organization of gene loci on gene regulation are linked through TAD architecture, and that mitosis is critical for establishing nuclear topologies during cellular differentiation.

Genomic organization and dynamics of repetitive DNA sequences in representatives of three Fagaceae genera

Genome ◽  
2012 ◽  
Vol 55 (5) ◽  
pp. 348-359 ◽  
Author(s):  
Sofia Alves ◽  
Teresa Ribeiro ◽  
Vera Inácio ◽  
Margarida Rocheta ◽  
Leonor Morais-Cecílio
Keyword(s):  
Dna Sequences ◽  
Genome Organization ◽  
Genomic Organization ◽  
Fish Analysis ◽  
Genome Composition ◽  
Interphase Nuclei ◽  
Specific Primers ◽  
Important Species ◽  
The Relationship ◽  
Quercus Rotundifolia

Oaks, chestnuts, and beeches are economically important species of the Fagaceae. To understand the relationship between these members of this family, a deep knowledge of their genome composition and organization is needed. In this work, we have isolated and characterized several AFLP fragments obtained from Quercus rotundifolia Lam. through homology searches in available databases. Genomic polymorphisms involving some of these sequences were evaluated in two species of Quercus , one of Castanea , and one of Fagus with specific primers. Comparative FISH analysis with generated sequences was performed in interphase nuclei of the four species, and the co-immunolocalization of 5-methylcytosine was also studied. Some of the sequences isolated proved to be genus-specific, while others were present in all the genera. Retroelements, either gypsy-like of the Tat/Athila clade or copia-like, are well represented, and most are dispersed in euchromatic regions of these species with no DNA methylation associated, pointing to an interspersed arrangement of these retroelements with potential gene-rich regions. A particular gypsy-sequence is dispersed in oaks and chestnut nuclei, but its confinement to chromocenters in beech evidences genome restructuring events during evolution of Fagaceae. Several sequences generated in this study proved to be good tools to comparatively study Fagaceae genome organization.

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