scholarly journals Genome Compartmentalization with Nuclear Landmarks: Random yet Precise

2021 ◽  
Author(s):  
Kartik Kamat ◽  
Yifeng Qi ◽  
Yuchuan Wang ◽  
Jian Ma ◽  
Bin Zhang
Keyword(s):  
Phase Separation ◽  
Genome Organization ◽  
Large Scale ◽  
Three Dimensional ◽  
Nuclear Lamina ◽  
Spatial Arrangement ◽  
Nuclear Bodies ◽  
Chromatin Interaction ◽  
Nuclear Speckles ◽  
Heterogeneous Distribution

The three-dimensional (3D) organization of eukaryotic genomes plays an important role in genome function. While significant progress has been made in deciphering the folding mechanisms of individual chromosomes, the principles of the dynamic large-scale spatial arrangement of all chromosomes inside the nucleus are poorly understood. We use polymer simulations to model the diploid human genome compartmentalization relative to nuclear bodies such as nuclear lamina, nucleoli, and speckles. We show that a self-organization process based on a co-phase separation between chromosomes and nuclear bodies can capture various features of genome organization, including the formation of chromosome territories, phase separation of A/B compartments, and the liquid property of nuclear bodies. The simulated 3D structures quantitatively reproduce both sequencing-based genomic mapping and imaging assays that probe chromatin interaction with nuclear bodies. Importantly, our model captures the heterogeneous distribution of chromosome positioning across cells, while simultaneously producing well-defined distances between active chromatin and nuclear speckles. Such heterogeneity and preciseness of genome organization can coexist due to the non-specificity of phase separation and the slow chromosome dynamics. Together, our work reveals that the co-phase separation provides a robust mechanism for encoding functionally important 3D contacts without requiring thermodynamic equilibration that can be difficult to achieve.

scholarly journals TSA-Seq Mapping of Nuclear Genome Organization

2018 ◽  
Author(s):  
Yu Chen ◽  
Yang Zhang ◽  
Yuchuan Wang ◽  
Liguo Zhang ◽  
Eva K. Brinkman ◽  
...  
Keyword(s):  
Genome Organization ◽  
Spatial Organization ◽  
Essential Feature ◽  
Three Dimensional ◽  
Nuclear Genome ◽  
Nuclear Lamina ◽  
Mapping Method ◽  
Spatial Gradient ◽  
Nuclear Speckles ◽  
Genome Wide

SummaryWhile nuclear compartmentalization is an essential feature of three-dimensional genome organization, no genomic method exists for measuring chromosome distances to defined nuclear structures. Here we describe TSA-Seq, a new mapping method able to estimate mean chromosomal distances from nuclear speckles genome-wide and predict several Mbp chromosome trajectories between nuclear compartments without sophisticated computational modeling. Ensemble-averaged results reveal a clear nuclear lamina to speckle axis correlated with a striking spatial gradient in genome activity. This gradient represents a convolution of multiple, spatially separated nuclear domains, including two types of transcription “hot-zones”. Transcription hot-zones protruding furthest into the nuclear interior and positioning deterministically very close to nuclear speckles have higher numbers of total genes, the most highly expressed genes, house-keeping genes, genes with low transcriptional pausing, and super-enhancers. Our results demonstrate the capability of TSA-Seq for genome-wide mapping of nuclear structure and suggest a new model for nuclear spatial organization of transcription.

Phase Separation and Elastic Fields: Three Dimensional Simulations of a Phase Field Model

1999 ◽  
Vol 580 ◽  
Author(s):  
Daniel Orlikowski ◽  
Celeste Sagui ◽  
Andrds Somoza ◽  
Christopher Roland
Keyword(s):  
Phase Separation ◽  
Large Scale ◽  
Ostwald Ripening ◽  
Three Dimensional ◽  
Selection Criterion ◽  
Phase Field Model ◽  
Dynamic Scaling ◽  
Shear Moduli ◽  
Elastic Fields ◽  
Three Dimensional Simulations

AbstractThe effects of long-range elastic fields on the phase separation process of three- dimensional binary alloy systems was investigated with large-scale Langevin simulations. The elastic effects incorporated in the model are the result of anisotropy and dilational misfits introduced via inhomogeneities in the elastic constants of the constituents. The domain morphology obtained is readily understandable in terms of selection criterion for the shape and/or orientation of the domains, and is based on the different shear moduli that are present in the system. Coarsening mechanisms were found to be a combination of the classical Ostwald ripening mechanism and the elastically-driven coalescence of domains. Other aspects of the coarsening process such as dynamic scaling of the structure function is presented.

Three-Dimensional Simulations of Phase Separation in Model Binary Alloy Systems with Elasticity

1997 ◽  
Vol 481 ◽  
Author(s):  
D. Orlikowski ◽  
C. Sagui ◽  
A. S. Somoza ◽  
C. Roland
Keyword(s):  
Phase Separation ◽  
Binary Alloy ◽  
Large Scale ◽  
Three Dimensional ◽  
Elastic Field ◽  
Dimensional System ◽  
Elastic Fields ◽  
Slowing Down ◽  
Three Dimensional Simulations ◽  
Alloy Systems

ABSTRACTWe report on large-scale three-dimensional simulations of phase separation in model binary alloy systems in the presence of elastic fields. The elastic field has several important effects on the morphology of the system: the ordered domains are subject to shape transformations, and spatial ordering. In contrast to two-dimensional system, no significant slowing down in the growth is observed. There is also no evidence of any “reverse coarsening” of the domains.

scholarly journals Assessing relationships between chromatin interactions and regulatory genomic activities using the self-organizing map

2020 ◽  
Author(s):  
Timothy Kunz ◽  
Lila Rieber ◽  
Shaun Mahony
Keyword(s):  
Genome Organization ◽  
Dimensional Space ◽  
Three Dimensional ◽  
Interaction Space ◽  
The Self ◽  
Chromatin Interaction ◽  
High Dimensional ◽  
Self Organizing Map ◽  
Two Dimensional ◽  
Chromatin Interactions

ABSTRACTFew existing methods enable the visualization of relationships between regulatory genomic activities and genome organization as captured by Hi-C experimental data. Genome-wide Hi-C datasets are often displayed using “heatmap” matrices, but it is difficult to intuit from these heatmaps which biochemical activities are compartmentalized together. High-dimensional Hi-C data vectors can alternatively be projected onto three-dimensional space using dimensionality reduction techniques. The resulting three-dimensional structures can serve as scaffolds for projecting other forms of genomic information, thereby enabling the exploration of relationships between genome organization and various genome annotations. However, while three-dimensional models are contextually appropriate for chromatin interaction data, some analyses and visualizations may be more intuitively and conveniently performed in two-dimensional space.We present a novel approach to the visualization and analysis of chromatin organization based on the Self-Organizing Map (SOM). The SOM algorithm provides a two-dimensional manifold which adapts to represent the high dimensional chromatin interaction space. The resulting data structure can then be used to assess the relationships between regulatory genomic activities and chromatin interactions. For example, given a set of genomic coordinates corresponding to a given biochemical activity, the degree to which this activity is segregated or compartmentalized in chromatin interaction space can be intuitively visualized on the 2D SOM grid and quantified using Lorenz curve analysis. We demonstrate our approach for exploratory analysis of genome compartmentalization in a high-resolution Hi-C dataset from the human GM12878 cell line. Our SOM-based approach provides an intuitive visualization of the large-scale structure of Hi-C data and serves as a platform for integrative analyses of the relationships between various genomic activities and genome organization.

scholarly journals Lamins organize the global three-dimensional genome from the nuclear periphery

2017 ◽  
Author(s):  
Xiaobin Zheng ◽  
Jiabiao Hu ◽  
Sibiao Yue ◽  
Lidya Kristiani ◽  
Miri Kim ◽  
...  
Keyword(s):  
Genome Organization ◽  
Es Cells ◽  
Nuclear Periphery ◽  
Three Dimensional ◽  
Nuclear Lamina ◽  
Chromatin Domain ◽  
List Type ◽  
Chromatin Domains ◽  
Mouse Es Cells ◽  
Domain Interactions

AbstractLamins are structural components of the nuclear lamina (NL) that regulate genome organization and gene expression, but the mechanism remains unclear. Using Hi-C, we show that lamins maintain proper interactions among the topologically associated chromatin domains (TADs) but not their overall architecture. Combining Hi-C with fluorescence in situ hybridization (FISH) and analyses of lamina-associated domains (LADs), we reveal that lamin loss causes expansion or detachment of specific LADs in mouse ES cells. The detached LADs disrupt 3D interactions of both LADs and interior chromatin. 4C and epigenome analyses further demonstrate that lamins maintain the active and repressive chromatin domains among different TADs. By combining these studies with transcriptome analyses, we found a significant correlation between transcription changes and the changes of active and inactive chromatin domain interactions. These findings provide a foundation to further study how the nuclear periphery impacts genome organization and transcription in development and NL-associated diseases.HighlightsLamin loss does not affect the overall TAD structure but alters TAD-TAD interactionsLamin null ES cells exhibit decondensation or detachment of specific LAD regionsExpansion and detachment of LADs can alter genome-wide 3D chromatin interactionsAltered chromatin domain interactions are correlated with altered transcription

scholarly journals Understanding nanoscale structural distortions in Pb(Zr0.2Ti0.8)O3 by utilizing X-ray nanodiffraction and clustering algorithm analysis

2021 ◽  
Vol 28 (1) ◽  
pp. 207-213
Author(s):  
Joyce Christiansen-Salameh ◽  
Morris Yang ◽  
Geoffrey Rippy ◽  
Jianheng Li ◽  
Zhonghou Cai ◽  
...  
Keyword(s):  
Phase Separation ◽  
Clustering Algorithm ◽  
Three Dimensional ◽  
Local Strain ◽  
Lattice Parameters ◽  
Algorithm Analysis ◽  
Nondestructive Technique ◽  
Heterogeneous Distribution ◽  
X Ray ◽  
Structural Distortions

Hard X-ray nanodiffraction provides a unique nondestructive technique to quantify local strain and structural inhomogeneities at nanometer length scales. However, sample mosaicity and phase separation can result in a complex diffraction pattern that can make it challenging to quantify nanoscale structural distortions. In this work, a k-means clustering algorithm was utilized to identify local maxima of intensity by partitioning diffraction data in a three-dimensional feature space of detector coordinates and intensity. This technique has been applied to X-ray nanodiffraction measurements of a patterned ferroelectric PbZr0.2Ti0.8O3 sample. The analysis reveals the presence of two phases in the sample with different lattice parameters. A highly heterogeneous distribution of lattice parameters with a variation of 0.02 Å was also observed within one ferroelectric domain. This approach provides a nanoscale survey of subtle structural distortions as well as phase separation in ferroelectric domains in a patterned sample.

scholarly journals ARID1A spatially partitions interphase chromosomes

2019 ◽  
Vol 5 (5) ◽  
pp. eaaw5294 ◽  
Author(s):  
Shuai Wu ◽  
Nail Fatkhutdinov ◽  
Leah Rosin ◽  
Jennifer M. Luppino ◽  
Osamu Iwasaki ◽  
...  
Keyword(s):  
Genome Organization ◽  
Large Scale ◽  
Three Dimensional ◽  
Higher Order ◽  
Interphase Chromosome ◽  
Chromatin Remodeling Complex ◽  
Chromosome Partitioning ◽  
Topologically Associated Domains ◽  
A Subunit

ARID1A, a subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex, localizes to both promoters and enhancers to influence transcription. However, the role of ARID1A in higher-order spatial chromosome partitioning and genome organization is unknown. Here, we show that ARID1A spatially partitions interphase chromosomes and regulates higher-order genome organization. The SWI/SNF complex interacts with condensin II, and they display significant colocalizations at enhancers. ARID1A knockout drives the redistribution of condensin II preferentially at enhancers, which positively correlates with changes in transcription. ARID1A and condensin II contribute to transcriptionally inactive B-compartment formation, while ARID1A weakens the border strength of topologically associated domains. Condensin II redistribution induced by ARID1A knockout positively correlates with chromosome sizes, which negatively correlates with interchromosomal interactions. ARID1A loss increases the trans interactions of small chromosomes, which was validated by three-dimensional interphase chromosome painting. These results demonstrate that ARID1A is important for large-scale genome folding and spatially partitions interphase chromosomes.

scholarly journals Tcf1 and Lef1 provide constant supervision to mature CD8+ T cell identity and function by organizing genomic architecture

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qiang Shan ◽  
Xiang Li ◽  
Xia Chen ◽  
Zhouhao Zeng ◽  
Shaoqi Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Genome Organization ◽  
Multiple Scales ◽  
Three Dimensional ◽  
Chromatin Interaction ◽  
Cell Identity ◽  
Chromosome Conformation ◽  
Network Analyses ◽  
And Function

AbstractT cell identity is established during thymic development, but how it is maintained in the periphery remains unknown. Here we show that ablating Tcf1 and Lef1 transcription factors in mature CD8+ T cells aberrantly induces genes from non-T cell lineages. Using high-throughput chromosome-conformation-capture sequencing, we demonstrate that Tcf1/Lef1 are important for maintaining three-dimensional genome organization at multiple scales in CD8+ T cells. Comprehensive network analyses coupled with genome-wide profiling of chromatin accessibility and Tcf1 occupancy show the direct impact of Tcf1/Lef1 on the T cell genome is to promote formation of extensively interconnected hubs through enforcing chromatin interaction and accessibility. The integrative mechanisms utilized by Tcf1/Lef1 underlie activation of T cell identity genes and repression of non-T lineage genes, conferring fine control of various T cell functionalities. These findings suggest that Tcf1/Lef1 control global genome organization and help form intricate chromatin-interacting hubs to facilitate promoter-enhancer/silencer contact, hence providing constant supervision of CD8+ T cell identity and function.

scholarly journals Higher-order inter-chromosomal hubs shape 3-dimensional genome organization in the nucleus

2017 ◽  
Author(s):  
Sofia A. Quinodoz ◽  
Noah Ollikainen ◽  
Barbara Tabak ◽  
Ali Palla ◽  
Jan Marten Schmidt ◽  
...  
Keyword(s):  
Genome Organization ◽  
Genomic Dna ◽  
Spatial Association ◽  
Higher Order ◽  
Nuclear Bodies ◽  
Dimensional Structure ◽  
Nuclear Speckles ◽  
3 Dimensional ◽  
Proximity Ligation ◽  
Genome Wide

ABSTRACTEukaryotic 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.

scholarly journals Profiling of 3D Genome Organization in Nasopharyngeal Cancer Needle Biopsy Patient Samples by a Modified Hi-C Approach

2021 ◽  
Vol 12 ◽  
Author(s):  
Sambhavi Animesh ◽  
Ruchi Choudhary ◽  
Bertrand Jern Han Wong ◽  
Charlotte Tze Jia Koh ◽  
Xin Yi Ng ◽  
...  
Keyword(s):  
Genome Organization ◽  
Needle Biopsy ◽  
Nasopharyngeal Cancer ◽  
Three Dimensional ◽  
Chromatin Interaction ◽  
Solid Cancer ◽  
3D Genome ◽  
Chromatin Interactions ◽  
Super Enhancer ◽  
Topologically Associated Domains

Nasopharyngeal cancer (NPC), a cancer derived from epithelial cells in the nasopharynx, is a cancer common in China, Southeast Asia, and Africa. The three-dimensional (3D) genome organization of nasopharyngeal cancer is poorly understood. A major challenge in understanding the 3D genome organization of cancer samples is the lack of a method for the characterization of chromatin interactions in solid cancer needle biopsy samples. Here, we developed Biop-C, a modified in situ Hi-C method using solid cancer needle biopsy samples. We applied Biop-C to characterize three nasopharyngeal cancer solid cancer needle biopsy patient samples. We identified topologically associated domains (TADs), chromatin interaction loops, and frequently interacting regions (FIREs) at key oncogenes in nasopharyngeal cancer from the Biop-C heatmaps. We observed that the genomic features are shared at some important oncogenes, but the patients also display extensive heterogeneity at certain genomic loci. On analyzing the super enhancer landscape in nasopharyngeal cancer cell lines, we found that the super enhancers are associated with FIREs and can be linked to distal genes via chromatin loops in NPC. Taken together, our results demonstrate the utility of our Biop-C method in investigating 3D genome organization in solid cancers.

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