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 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 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.

The 3D Genome Structure of Single Cells

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Tianming Zhou ◽  
Ruochi Zhang ◽  
Jian Ma
Keyword(s):  
Single Cell ◽  
Data Science ◽  
Spatial Organization ◽  
Method Development ◽  
Single Cells ◽  
Genome Structure ◽  
Computational Method ◽  
Publication Date ◽  
3D Genome ◽  
Genome Features

The spatial organization of the genome in the cell nucleus is pivotal to cell function. However, how the 3D genome organization and its dynamics influence cellular phenotypes remains poorly understood. The very recent development of single-cell technologies for probing the 3D genome, especially single-cell Hi-C (scHi-C), has ushered in a new era of unveiling cell-to-cell variability of 3D genome features at an unprecedented resolution. Here, we review recent developments in computational approaches to the analysis of scHi-C, including data processing, dimensionality reduction, imputation for enhancing data quality, and the revealing of 3D genome features at single-cell resolution. While much progress has been made in computational method development to analyze single-cell 3D genomes, substantial future work is needed to improve data interpretation and multimodal data integration, which are critical to reveal fundamental connections between genome structure and function among heterogeneous cell populations in various biological contexts. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 4 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Capturing cell type-specific chromatin structural patterns by applying topic modeling to single-cell Hi-C data

2019 ◽  
Author(s):  
Hyeon-Jin Kim ◽  
Galip Gürkan Yardımcı ◽  
Giancarlo Bonora ◽  
Vijay Ramani ◽  
Jie Liu ◽  
...  
Keyword(s):  
Single Cell ◽  
Topic Modeling ◽  
Biological Information ◽  
Chromatin Interaction ◽  
Cell Type ◽  
3D Genome ◽  
Genome Wide ◽  
Significant Barrier ◽  
Chromatin Structural ◽  
Cell Type Specific

AbstractSingle-cell Hi-C (scHi-C) interrogates genome-wide chromatin interaction in individual cells, allowing us to gain insights into 3D genome organization. However, the extremely sparse nature of scHi-C data poses a significant barrier to analysis, limiting our ability to tease out hidden biological information. In this work, we approach this problem by applying topic modeling to scHi-C data. Topic modeling is well-suited for discovering latent topics in a collection of discrete data. For our analysis, we generate twelve different single-cell combinatorial indexed Hi-C (sciHi-C) libraries from five human cell lines (GM12878, H1Esc, HFF, IMR90, and HAP1), consisting over 25,000 cells. We demonstrate that topic modeling is able to successfully capture cell type differences from sciHi-C data in the form of “chromatin topics.” We further show enrichment of particular compartment structures associated with locus pairs in these topics.

Antibody-free profiling of transcription factor occupancy during early embryogenesis by FitCUT&RUN

2021 ◽  
pp. gr.275837.121
Author(s):  
Xiangxiu Wang ◽  
Wen Wang ◽  
Yiman Wang ◽  
Jia Chen ◽  
Guifen Liu ◽  
...  
Keyword(s):  
Significant Proportion ◽  
K562 Cells ◽  
Replication Timing ◽  
Early Embryogenesis ◽  
Clear Trend ◽  
Genome Wide ◽  
Sequential Binding ◽  
Reliability And Robustness ◽  
Genome Activation ◽  
Transcription Factor Occupancy

Key transcription factors (TFs) play critical roles in zygotic genome activation (ZGA) during early embryogenesis, while genome-wide occupancies of only a few factors have been profiled during ZGA due to the limitation of cell numbers or the lack of high-quality antibodies. Here, we present FitCUT&RUN, a modified CUT&RUN method, in which an Fc fragment of immunoglobulin G is used for tagging, to profile TF occupancy in an antibody-free manner and demonstrate its reliability and robustness using as few as five thousand K562 cells. We applied FitCUT&RUN to zebrafish undergoing embryogenesis to generate reliable occupancy profiles of three known activators of zebrafish ZGA: Nanog, Pou5f3 and Sox19b. By profiling the time-series occupancy of Nanog during zebrafish ZGA, we observed a clear trend toward a gradual increase in Nanog occupancy and found that Nanog occupancy prior to the major phase of ZGA is critical for the activation of a significant proportion of early transcribed genes. Our results further suggested that the sequential binding of Nanog may be controlled by replication timing and the presence of Nanog motifs.

scholarly journals G2 phase chromatin lacks determinants of replication timing

2010 ◽  
Vol 189 (6) ◽  
pp. 967-980 ◽  
Author(s):  
Junjie Lu ◽  
Feng Li ◽  
Christopher S. Murphy ◽  
Michael W. Davidson ◽  
David M. Gilbert
Keyword(s):  
Spatial Organization ◽  
Replication Timing ◽  
S Phase ◽  
Decision Point ◽  
Genome Wide Analysis ◽  
Quiescent Cells ◽  
Egg Extract ◽  
Genome Wide ◽  
G2 Phase

DNA replication in all eukaryotes follows a defined replication timing program, the molecular mechanism of which remains elusive. Using a Xenopus laevis egg extract replication system, we previously demonstrated that replication timing is established during early G1 phase of the cell cycle (timing decision point [TDP]), which is coincident with the repositioning and anchorage of chromatin in the newly formed nucleus. In this study, we use this same system to show that G2 phase chromatin lacks determinants of replication timing but maintains the overall spatial organization of chromatin domains, and we confirm this finding by genome-wide analysis of rereplication in vivo. In contrast, chromatin from quiescent cells retains replication timing but exhibits disrupted spatial organization. These data support a model in which events at the TDP, facilitated by chromatin spatial organization, establish determinants of replication timing that persist independent of spatial organization until the process of chromatin replication during S phase erases those determinants.

scholarly journals Genome-wide stability of the DNA replication program in single mammalian cells

2017 ◽  
Author(s):  
Saori Takahashi ◽  
Hisashi Miura ◽  
Takahiro Shibata ◽  
Koji Nagao ◽  
Katsuzumi Okumura ◽  
...  
Keyword(s):  
Dna Replication ◽  
Mammalian Cells ◽  
Developmental Plasticity ◽  
Embryonic Stem ◽  
Replication Timing ◽  
Small Degree ◽  
3D Genome ◽  
Inactive X Chromosome ◽  
Genome Wide ◽  
Individual Mouse

ABSTRACTHere, we report the establishment of a single-cell DNA replication sequencing method, scRepli-seq, which is a simple genome-wide methodology that measures copy number differences between replicated and unreplicated DNA. Using scRepli-seq, we demonstrate that replication domain organization is conserved among individual mouse embryonic stem cells (mESCs). Differentiated mESCs exhibited distinct replication profiles, which were conserved from cell to cell. Haplotype-resolved scRepli-seq revealed similar replication timing profiles of homologous autosomes, while the inactive X chromosome was clearly replicated later than its active counterpart. However, a small degree of cell-to-cell replication timing heterogeneity was present, and we discovered that developmentally regulated domains are a source of such variability, suggesting a link between cell-to-cell heterogeneity and developmental plasticity. Together, our results form a foundation for single-cell-level understanding of DNA replication regulation and provide insights into 3D genome organization.

scholarly journals PGS: a dynamic and automated population-based genome structure software

2017 ◽  
Author(s):  
Nan Hua ◽  
Harianto Tjong ◽  
Hanjun Shin ◽  
Ke Gong ◽  
Xianghong Jasmine Zhou ◽  
...  
Keyword(s):  
High Performance ◽  
Spatial Organization ◽  
Genome Structure ◽  
Probabilistic Approach ◽  
Population Based ◽  
Chromatin Interaction ◽  
3D Analysis ◽  
3D Genome ◽  
A Genome ◽  
Contact Frequency

ABSTRACTHi-C technologies are widely used to investigate the spatial organization of genomes. However, the structural variability of the genome is a great challenge to interpreting ensemble-averaged Hi-C data, particularly for long-range/interchromosomal interactions. We pioneered a probabilistic approach for generating a population of distinct diploid 3D genome structures consistent with all the chromatin-chromatin interaction probabilities from Hi-C experiments. Each structure in the population is a physical model of the genome in 3D. Analysis of these models yields new insights into the causes and the functional properties of the genome’s organization in space and time. We provide a user-friendly software package, called PGS, that runs on local machines and high-performance computing platforms. PGS takes a genome-wide Hi-C contact frequency matrix and produces an ensemble of 3D genome structures entirely consistent with the input. The software automatically generates an analysis report, and also provides tools to extract and analyze the 3D coordinates of specific domains.

Chromosome interactome inferred from mitosis-G1 transition

2016 ◽  
Author(s):  
Y.A. Eidelman ◽  
S.V. Slanina ◽  
A.V. Aleshchenko ◽  
S.G. Andreev
Keyword(s):  
Spatial Organization ◽  
Contact Map ◽  
Interphase Chromosome ◽  
Basic Principles ◽  
Chromosome Conformation ◽  
3D Genome ◽  
Contact Patterns ◽  
Genome Wide ◽  
Genome Study ◽  
Contact Data

ABSTRACTThe progress in experimental techniques aimed at 3D genome study is yet to bring about revelation of basic principles of genome folding. Chromosome conformation capture Hi-C technologies provide genome wide mapping of genomic loci interactions but spatial organization of chromosomes remains unknown. Here, we develop a polymer modeling approach to generate the ensemble of 3D chromosome conformations for mapping genetic loci contacts and the positions of megabase chromosomal domains in interphase chromosome at different time of mitosis-interphase transition. We demonstrate that (*) whole chromosome contact map (interactome) generated for mouse chromosome 18 structure and (**) contact patterns, observed soon after mitotic decondensation and remaining similar during G1, correlate well with the experimental Hi-C contact data. The results suggest that contact map formation and spatial compartmentalization of an interphase chromosome are driven by interactions between different types of domains during formation of globular chromosome state at the end of mitotis-G1 transition.

scholarly journals Progerin impairs 3D genome organization and induces fragile telomeres by limiting the dNTP pools

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anna Kychygina ◽  
Marina Dall’Osto ◽  
Joshua A. M. Allen ◽  
Jean-Charles Cadoret ◽  
Vincent Piras ◽  
...  
Keyword(s):  
Genetic Disorder ◽  
Nuclear Lamina ◽  
Replication Timing ◽  
Premature Aging ◽  
Functional Connection ◽  
3D Genome ◽  
Genome Wide ◽  
Associated Proteins ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

AbstractChromatin organization within the nuclear volume is essential to regulate many aspects of its function and to safeguard its integrity. A key player in this spatial scattering of chromosomes is the nuclear envelope (NE). The NE tethers large chromatin domains through interaction with the nuclear lamina and other associated proteins. This organization is perturbed in cells from Hutchinson–Gilford progeria syndrome (HGPS), a genetic disorder characterized by premature aging features. Here, we show that HGPS-related lamina defects trigger an altered 3D telomere organization with increased contact sites between telomeres and the nuclear lamina, and an altered telomeric chromatin state. The genome-wide replication timing signature of these cells is perturbed, with a shift to earlier replication for regions that normally replicate late. As a consequence, we detected a higher density of replication forks traveling simultaneously on DNA fibers, which relies on limiting cellular dNTP pools to support processive DNA synthesis. Remarkably, increasing dNTP levels in HGPS cells rescued fragile telomeres, and improved the replicative capacity of the cells. Our work highlights a functional connection between NE dysfunction and telomere homeostasis in the context of premature aging.

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