The holocentric speciesLuzula elegansshows interplay between centromere and large-scale genome organization

AbstractGeneration of mature red blood cells, consisting mainly of hemoglobin, is a remarkable example of coordinated action of various signaling networks. Chromatin condensation is an essential step for terminal erythroid differentiation and subsequent nuclear expulsion in mammals. Here, we profiled 3D genome organization in the blood cells from ten species belonging to different vertebrate classes. Our analysis of contact maps revealed a striking absence of such 3D interaction patterns as loops or TADs in blood cells of all analyzed representatives. We also detect large-scale chromatin rearrangements in blood cells from mammals, birds, reptiles and amphibians: their contact maps display strong second diagonal pattern, representing an increased frequency of long-range contacts, unrelated to TADs or compartments. This pattern is completely atypical for interphase chromosome structure. We confirm that these principles of genome organization are conservative in vertebrate erythroid cells.

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Identification of decondensed large-scale chromatin regions by TSA-seq and their localization to a subset of chromatin domain boundaries

10.1101/2021.04.06.438686 ◽

2021 ◽

Author(s):

Omid Gholamalamdari ◽

Liguo Zhang ◽

Yu Chen ◽

Andrew Belmont

Keyword(s):

Genome Organization ◽

Large Scale ◽

Chromatin Domain ◽

Interphase Chromosome ◽

Chromatin Domains ◽

Nuclear Compartment ◽

Chromatin Compaction ◽

Domain Boundaries ◽

Chromatin Remodeling Complexes ◽

Local Enrichment

AbstractLarge-scale chromatin compaction is nonuniform across the human genome and correlates with gene expression and genome organization. Current methodologies for assessing large-scale chromatin compaction are indirect and largely based on assays that probe lower levels of chromatin organization, primarily at the level of the nucleosome and/or the local compaction of nearby nucleosomes. These assays assume a one-to-one correlation between local nucleosomal compaction and large-scale compaction of chromosomes that may not exist. Here we describe a method to identify interphase chromosome regions with relatively high levels of large-scale chromatin decondensation using TSA-seq, which produces a signal proportional to microscopic-scale distances relative to a defined nuclear compartment. TSA-seq scores that change rapidly as a function of genomic distance, detected by their higher slope values, identify decondensed large-scale chromatin domains (DLCDs), as then validated by 3D DNA-FISH. DLCDs map near a subset of chromatin domain boundaries, defined by Hi-C, which separate active and repressed chromatin domains and correspond to compartment, subcompartment, and some TAD boundaries. Most DLCDs can also be detected by high slopes of their Hi-C compartment score. In addition to local enrichment in cohesin (RAD21, SMC3) and CTCF, DLCDs show the highest local enrichment to super-enhancers, but are also locally enriched in transcription factors, histone-modifying complexes, chromatin mark readers, and chromatin remodeling complexes. The localization of these DLCDs to a subset of Hi-C chromatin domain boundaries that separate active versus inactive chromatin regions, as measured by two orthogonal genomic methods, suggests a distinct role for DLCDs in genome organization.

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Acute condensin depletion causes genome decompaction without altering the level of global gene expression in Saccharomyces cerevisiae

10.1101/195487 ◽

2017 ◽

Cited By ~ 2

Author(s):

Matthew Robert Paul ◽

Tovah Elise Markowitz ◽

Andreas Hochwagen ◽

Sevinç Ercan

Keyword(s):

Gene Expression ◽

Saccharomyces Cerevisiae ◽

Genome Organization ◽

Large Scale ◽

Global Gene Expression ◽

Higher Order ◽

Gene Clustering ◽

Global Changes ◽

Chromatin Compaction ◽

And Function

AbstractCondensins are broadly conserved chromosome organizers that function in chromatin compaction and transcriptional regulation, but to what extent these two functions are linked has remained unclear. Here, we analyzed the effect of condensin inactivation on genome compaction and global gene expression in the yeast Saccharomyces cerevisiae. Spike-in-controlled 3C-seq analysis revealed that acute condensin inactivation leads to a global decrease in close-range chromosomal interactions as well as more specific losses of homotypic tRNA gene clustering. In addition, a condensin-rich topologically associated domain between the ribosomal DNA and the centromere on chromosome XII is lost upon condensin inactivation. Unexpectedly, these large-scale changes in chromosome architecture are not associated with global changes in transcript levels as determined by spike-in-controlled mRNA-seq analysis. Our data suggest that the global transcriptional program of S. cerevisiae is resistant to condensin inactivation and the associated profound changes in genome organization.Significance StatementGene expression occurs in the context of higher-order chromatin organization, which helps compact the genome within the spatial constraints of the nucleus. To what extent higher-order chromatin compaction affects gene expression remains unknown. Here, we show that gene expression and genome compaction can be uncoupled in the single-celled model eukaryote Saccharomyces cerevisiae. Inactivation of the conserved condensin complex, which also organizes the human genome, leads to broad genome decompaction in this organism. Unexpectedly, this reorganization has no immediate effect on the transcriptome. These findings indicate that the global gene expression program is robust to large-scale changes in genome architecture in yeast, shedding important new light on the evolution and function of genome organization in gene regulation.

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A MODEL OF LARGE-SCALE PROTEOME EVOLUTION

Advances in Complex Systems ◽

10.1142/s021952590200047x ◽

2002 ◽

Vol 05 (01) ◽

pp. 43-54 ◽

Cited By ~ 197

Author(s):

RICARD V. SOLÉ ◽

ROMUALDO PASTOR-SATORRAS ◽

ERIC SMITH ◽

THOMAS B. KEPLER

Keyword(s):

Simple Model ◽

Protein Interactions ◽

Genome Organization ◽

Selection Pressure ◽

Large Scale ◽

Protein Protein Interactions ◽

Yeast Proteome ◽

Statistical Regularities ◽

Complete Sequences

The next step in the understanding of the genome organization, after the determination of complete sequences, involves proteomics. The proteome includes the whole set of protein-protein interactions, and two recent independent studies have shown that its topology displays a number of surprising features shared by other complex networks, both natural and artificial. In order to understand the origins of this topology and its evolutionary implications, we present a simple model of proteome evolution that is able to reproduce many of the observed statistical regularities reported from the analysis of the yeast proteome. Our results suggest that the observed patterns can be explained by a process of gene duplication and diversification that would evolve proteome networks under a selection pressure, favoring robustness against failure of its individual components.

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Genome Compartmentalization with Nuclear Landmarks: Random yet Precise

10.1101/2021.11.12.468401 ◽

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.

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Genomic organization underlying deletional robustness in bacterial metabolic systems

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1717243115 ◽

2018 ◽

Vol 115 (27) ◽

pp. 7075-7080 ◽

Cited By ~ 3

Author(s):

Sayed-Rzgar Hosseini ◽

Andreas Wagner

Keyword(s):

Genome Organization ◽

Large Scale ◽

Gene Loss ◽

Bacterial Genome ◽

Bacterial Populations ◽

Gene Deletions ◽

Metabolic Gene ◽

Metabolic Genes ◽

Metabolic Systems ◽

Adaptive Processes

Large-scale DNA deletions and gene loss are pervasive in bacterial genomes. This observation raises the possibility that evolutionary adaptation has altered bacterial genome organization to increase its robustness to large-scale tandem gene deletions. To find out, we systematically analyzed 55 bacterial genome-scale metabolisms and showed that metabolic gene ordering renders an organism’s viability in multiple nutrient environments significantly more robust against tandem multigene deletions than expected by chance. This excess robustness is caused by multiple factors, which include the clustering of essential metabolic genes, a greater-than-expected distance of synthetically lethal metabolic gene pairs, and the clustering of nonessential metabolic genes. By computationally creating minimal genomes, we show that a nonadaptive origin of such clustering could in principle arise as a passive byproduct of bacterial genome growth. However, because genome randomization forces such as translocation and inversion would eventually erode such clustering, adaptive processes are necessary to sustain it. We provide evidence suggesting that this organization might result from adaptation to ongoing gene deletions, and from selective advantages associated with coregulating functionally related genes. Horizontal gene transfer in the presence of gene deletions contributes to sustaining the clustering of essential genes. In sum, our observations suggest that the genome organization of bacteria is driven by adaptive processes that provide phenotypic robustness in response to large-scale gene deletions. This robustness may be especially important for bacterial populations that take advantage of gene loss to adapt to new environments.

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The Myc-associated zinc finger protein (MAZ) works together with CTCF to control cohesin positioning and genome organization

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2023127118 ◽

2021 ◽

Vol 118 (7) ◽

pp. e2023127118

Author(s):

Tiaojiang Xiao ◽

Xin Li ◽

Gary Felsenfeld

Keyword(s):

Rna Polymerase Ii ◽

Zinc Finger ◽

Binding Sites ◽

Genome Organization ◽

Large Scale ◽

Zinc Finger Protein ◽

Ctcf Binding ◽

Finger Protein ◽

Topologically Associated Domains ◽

Cohesin Subunit

The Myc-associated zinc finger protein (MAZ) is often found at genomic binding sites adjacent to CTCF, a protein which affects large-scale genome organization through its interaction with cohesin. We show here that, like CTCF, MAZ physically interacts with a cohesin subunit and can arrest cohesin sliding independently of CTCF. It also shares with CTCF the ability to independently pause the elongating form of RNA polymerase II, and consequently affects RNA alternative splicing. CTCF/MAZ double sites are more effective at sequestering cohesin than sites occupied only by CTCF. Furthermore, depletion of CTCF results in preferential loss of CTCF from sites not occupied by MAZ. In an assay for insulation activity like that used for CTCF, binding of MAZ to sites between an enhancer and promoter results in down-regulation of reporter gene expression, supporting a role for MAZ as an insulator protein. Hi-C analysis of the effect of MAZ depletion on genome organization shows that local interactions within topologically associated domains (TADs) are disrupted, as well as contacts that establish the boundaries of individual TADs. We conclude that MAZ augments the action of CTCF in organizing the genome, but also shares properties with CTCF that allow it to act independently.

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ARID1A spatially partitions interphase chromosomes

Science Advances ◽

10.1126/sciadv.aaw5294 ◽

2019 ◽

Vol 5 (5) ◽

pp. eaaw5294 ◽

Cited By ~ 9

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.

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Data-driven polymer model for mechanistic exploration of diploid genome organization

10.1101/2020.02.27.968735 ◽

2020 ◽

Cited By ~ 1

Author(s):

Yifeng Qi ◽

Alejandro Reyes ◽

Sarah E. Johnstone ◽

Martin J. Aryee ◽

Bradley E. Bernstein ◽

...

Keyword(s):

Nuclear Localization ◽

Genome Organization ◽

Large Scale ◽

Transcriptional Activity ◽

Molecular Mechanisms ◽

Mechanistic Model ◽

Genome Structure ◽

Data Driven ◽

Experimental Measurements ◽

Polymer Model

AbstractChromosomes 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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Hi-C-constrained physical models of human chromosomes recover functionally-related properties of genome organization

10.1101/079558 ◽

2016 ◽

Author(s):

Marco Di Stefano ◽

Jonas Paulsen ◽

Tonje G. Lien ◽

Eivind Hovig ◽

Cristian Micheletti

Keyword(s):

Data Analysis ◽

Genome Organization ◽

Large Scale ◽

Three Dimensional ◽

Active Regions ◽

Physical Modelling ◽

Physical Models ◽

Contact Data ◽

Functional Features

ABSTRACTCombining genome-wide structural models with phenomenological data is at the forefront of efforts to understand the organizational principles regulating the human genome. Here, we use chromosome-chromosome contact data as knowledge- based constraints for large-scale three-dimensional models of the human diploid genome. The resulting models remain minimally entangled and acquire several functional features that are observed in vivo and that were never used as input for the model. We find, for instance, that gene-rich, active regions are drawn towards the nuclear center, while gene poor and lamina-associated domains are pushed to the periphery. These and other properties persist upon adding local contact constraints, suggesting their compatibility with non-local constraints for the genome organization. The results show that suitable combinations of data analysis and physical modelling can expose the unexpectedly rich functionally-related properties implicit in chromosome-chromosome contact data. Specific directions are suggested for further developments based on combining experimental data analysis and genomic structural modelling.

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