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.

scholarly journals Mapping 3D genome organization relative to nuclear compartments using TSA-Seq as a cytological ruler

2018 ◽  
Vol 217 (11) ◽  
pp. 4025-4048 ◽  
Author(s):  
Yu Chen ◽  
Yang Zhang ◽  
Yuchuan Wang ◽  
Liguo Zhang ◽  
Eva K. Brinkman ◽  
...  
Keyword(s):  
Genome Organization ◽  
Spatial Organization ◽  
Essential Feature ◽  
K562 Cells ◽  
Housekeeping Genes ◽  
Mapping Method ◽  
Spatial Gradient ◽  
Nuclear Speckles ◽  
Nuclear Compartments ◽  
Genome Wide

While nuclear compartmentalization is an essential feature of three-dimensional genome organization, no genomic method exists for measuring chromosome distances to defined nuclear structures. In this study, we describe TSA-Seq, a new mapping method capable of providing a “cytological ruler” for estimating mean chromosomal distances from nuclear speckles genome-wide and for predicting several Mbp chromosome trajectories between nuclear compartments without sophisticated computational modeling. Ensemble-averaged results in K562 cells 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, housekeeping 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 spatial organization of transcription and gene expression.

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 In silico prediction of high-resolution Hi-C interaction matrices

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Shilu Zhang ◽  
Deborah Chasman ◽  
Sara Knaack ◽  
Sushmita Roy
Keyword(s):  
High Resolution ◽  
Genome Organization ◽  
Three Dimensional ◽  
Predictive Performance ◽  
Computational Prediction ◽  
3D Genome ◽  
Genome Wide ◽  
Binding Factor ◽  
Sequence Elements ◽  
Individual Locus

AbstractThe three-dimensional (3D) organization of the genome plays an important role in gene regulation bringing distal sequence elements in 3D proximity to genes hundreds of kilobases away. Hi-C is a powerful genome-wide technique to study 3D genome organization. Owing to experimental costs, high resolution Hi-C datasets are limited to a few cell lines. Computational prediction of Hi-C counts can offer a scalable and inexpensive approach to examine 3D genome organization across multiple cellular contexts. Here we present HiC-Reg, an approach to predict contact counts from one-dimensional regulatory signals. HiC-Reg predictions identify topologically associating domains and significant interactions that are enriched for CCCTC-binding factor (CTCF) bidirectional motifs and interactions identified from complementary sources. CTCF and chromatin marks, especially repressive and elongation marks, are most important for HiC-Reg’s predictive performance. Taken together, HiC-Reg provides a powerful framework to generate high-resolution profiles of contact counts that can be used to study individual locus level interactions and higher-order organizational units of the genome.

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 Quantification of the Spatial Organization of the Nuclear Lamina as a Tool for Cell Classification

2013 ◽  
Vol 2013 ◽  
pp. 1-6
Author(s):  
Christiaan H. Righolt ◽  
Diana A. Zatreanu ◽  
Vered Raz
Keyword(s):  
Nuclear Envelope ◽  
Spatial Organization ◽  
Structural Changes ◽  
Structural Integrity ◽  
Quantitative Description ◽  
Three Dimensional ◽  
Nuclear Lamina ◽  
Cellular Functions ◽  
Cell Classification ◽  
Nuclear Stability

The nuclear lamina is the structural scaffold of the nuclear envelope that plays multiple regulatory roles in chromatin organization and gene expression as well as a structural role in nuclear stability. The lamina proteins, also referred to as lamins, determine nuclear lamina organization and define the nuclear shape and the structural integrity of the cell nucleus. In addition, lamins are connected with both nuclear and cytoplasmic structures forming a dynamic cellular structure whose shape changes upon external and internal signals. When bound to the nuclear lamina, the lamins are mobile, have an impact on the nuclear envelop structure, and may induce changes in their regulatory functions. Changes in the nuclear lamina shape cause changes in cellular functions. A quantitative description of these structural changes could provide an unbiased description of changes in cellular function. In this review, we describe how changes in the nuclear lamina can be measured from three-dimensional images of lamins at the nuclear envelope, and we discuss how structural changes of the nuclear lamina can be used for cell classification.

scholarly journals SPIN reveals genome-wide landscape of nuclear compartmentalization

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yuchuan Wang ◽  
Yang Zhang ◽  
Ruochi Zhang ◽  
Tom van Schaik ◽  
Liguo Zhang ◽  
...  
Keyword(s):  
Spatial Organization ◽  
K562 Cells ◽  
Replication Timing ◽  
Computational Method ◽  
Chromatin Interaction ◽  
Nuclear Speckles ◽  
Genome Spatial Organization ◽  
3D Genome ◽  
Genome Wide ◽  
Nuclear Compartmentalization

AbstractWe report SPIN, an integrative computational method to reveal genome-wide intranuclear chromosome positioning and nuclear compartmentalization relative to multiple nuclear structures, which are pivotal for modulating genome function. As a proof-of-principle, we use SPIN to integrate nuclear compartment mapping (TSA-seq and DamID) and chromatin interaction data (Hi-C) from K562 cells to identify 10 spatial compartmentalization states genome-wide relative to nuclear speckles, lamina, and putative associations with nucleoli. These SPIN states show novel patterns of genome spatial organization and their relation to other 3D genome features and genome function (transcription and replication timing). SPIN provides critical insights into nuclear spatial and functional compartmentalization.

scholarly journals Spatial Organization of Chromatin: Emergence of Chromatin Structure During Development

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Rajarshi P. Ghosh ◽  
Barbara J. Meyer
Keyword(s):  
Single Molecule ◽  
Genome Organization ◽  
Spatial Organization ◽  
Super Resolution ◽  
Annual Review ◽  
Publication Date ◽  
Cellular Processes ◽  
Regulatory Processes ◽  
Genome Wide ◽  
Resolution Imaging

Nuclei are central hubs for information processing in eukaryotic cells. The need to fit large genomes into small nuclei imposes severe restrictions on genome organization and the mechanisms that drive genome-wide regulatory processes. How a disordered polymer such as chromatin, which has vast heterogeneity in its DNA and histone modification profiles, folds into discernibly consistent patterns is a fundamental question in biology. Outstanding questions include how genomes are spatially and temporally organized to regulate cellular processes with high precision and whether genome organization is causally linked to transcription regulation. The advent of next-generation sequencing, super-resolution imaging, multiplexed fluorescent in situ hybridization, and single-molecule imaging in individual living cells has caused a resurgence in efforts to understand the spatiotemporal organization of the genome. In this review, we discuss structural and mechanistic properties of genome organization at different length scales and examine changes in higher-order chromatin organization during important developmental transitions. Expected final online publication date for the Annual Review of Cell and Developmental Biology, Volume 37 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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 SPIN reveals genome-wide landscape of nuclear compartmentalization

2020 ◽  
Author(s):  
Yuchuan Wang ◽  
Yang Zhang ◽  
Ruochi Zhang ◽  
Tom van Schaik ◽  
Liguo Zhang ◽  
...  
Keyword(s):  
Spatial Organization ◽  
K562 Cells ◽  
Replication Timing ◽  
Cell Types ◽  
Chromatin Interaction ◽  
Spin States ◽  
Nuclear Speckles ◽  
Genome Spatial Organization ◽  
Genome Wide ◽  
Nuclear Structures

AbstractChromosomes segregate differentially relative to distinct subnuclear structures, but this genome-wide compartmentalization, pivotal for modulating genome function, remains poorly understood. New genomic mapping methods can reveal chromosome positioning relative to specific nuclear structures. However, computational methods that integrate their results to identify overall intranuclear chromo-some positioning have not yet been developed. We report SPIN, a new method to identify genome-wide nuclear spatial localization patterns. As a proof-of-principle, we use SPIN to integrate nuclear compartment mapping (TSA-seq and DamID) and chromatin interaction data (Hi-C) from K562 cells to identify 10 spatial compartmentalization states genome-wide relative to nuclear speckles, lamina, and nucleoli. These SPIN states show novel patterns of genome spatial organization and their relation to genome function (transcription and replication timing). Comparisons of SPIN states with Hi-C sub-compartments and lamina-associated domains (LADs) from multiple cell types suggest constitutive compartmentalization patterns. By integrating different readouts of higher-order genome organization, SPIN provides critical insights into nuclear spatial and functional compartmentalization.

scholarly journals G9a/GLP-Sensitivity of H3K9me2 Demarcates Two Types of Genomic Compartments

2020 ◽  
Author(s):  
Zixiang Yan ◽  
Luzhang Ji ◽  
Xiangru Huo ◽  
Qianfeng Wang ◽  
Yuwen Zhang ◽  
...  
Keyword(s):  
Genome Organization ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Embryonic Stem ◽  
Nuclear Lamina ◽  
Hierarchical Architecture ◽  
Functional Roles ◽  
3D Genome ◽  
Differentiated Cells ◽  
Mouse Hepatocytes

AbstractIn the nucleus, chromatin is folded into hierarchical architecture that is tightly linked to various nuclear functions. However, the underlying molecular mechanisms that confer these architectures remain incompletely understood. Here, we investigated the functional roles of H3 lysine 9 dimethylation (H3K9me2), one of the abundant histone modifications, in three-dimensional (3D) genome organization. Unlike mouse embryonic stem cells (mESCs), inhibition of methyltransferases G9a and GLP in differentiated cells eliminated H3K9me2 predominantly at A-type (active) genomic compartments, and the level of residual H3K9me2 modification was strongly associated with genomic compartments in differentiated cells. Furthermore, chemical inhibition of G9a/GLP in mouse hepatocytes led to the decreased chromatin-nuclear lamina interactions mainly at G9a/GLP sensitive regions (GSRs), the increased degree of genomic compartmentalization, and the up-regulation of hundreds of genes that were associated with alterations of the 3D chromatin. Collectively, our data demonstrated essential roles of H3K9me2 in 3D genome organization.

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