Spatial organization of chromosomes leads to heterogeneous chromatin motion and drives the liquid- or gel-like dynamical behavior of chromatin

2021 ◽  
Author(s):  
Hossein Salari ◽  
Marco Di Stefano ◽  
Daniel Jost
Keyword(s):  
Spatial Organization ◽  
Dynamical Behavior ◽  
Coherent Motion ◽  
Cell Nuclei ◽  
Weakly Compact ◽  
Local Degree ◽  
Unified View ◽  
Key Driver ◽  
Structural Mechanisms ◽  
Two Sides

Chromosome organization and dynamics are involved in regulating many fundamental processes such as gene transcription and DNA repair. Experiments unveiled that chromatin motion is highly heterogeneous inside cell nuclei, ranging from a liquid-like, mobile state to a gel-like, rigid regime. Using polymer modeling, we investigate how these different physical states and dynamical heterogeneities may emerge from the same structural mechanisms. We found that the formation of topologically associating domains (TADs) is a key driver of chromatin motion heterogeneity. In particular, we showed that the local degree of compaction of the TAD regulates the transition from a weakly compact, fluid state of chromatin to a more compact, gel state exhibiting anomalous diffusion and coherent motion. Our work provides a comprehensive study of chromosome dynamics and a unified view of chromatin motion enabling interpretation of the wide variety of dynamical behaviors observed experimentally across different biological conditions, suggesting that the “liquid” or “solid” state of chromatin are in fact two sides of the same coin.

scholarly journals Spatial organization of chromosomes leads to heterogeneous chromatin motion and drives the liquid- or gel-like behavior of chromatin

2021 ◽  
Author(s):  
Hossein Salari ◽  
Marco Di Stefano ◽  
Daniel Jost
Keyword(s):  
Spatial Organization ◽  
Coherent Motion ◽  
Cell Nuclei ◽  
Weakly Compact ◽  
Local Degree ◽  
Dynamical Behaviors ◽  
Unified View ◽  
Key Driver ◽  
Structural Mechanisms ◽  
Comprehensive Study

Chromosome organization and dynamics are involved in the regulation of many fundamental processes such as gene transcription and DNA repair. Experiments unveiled that inside cell nuclei chromatin motion is highly heterogeneous ranging from a liquid-like, mobile state to a gel-like, rigid state. Using polymer modeling, we investigated how these different physical states and dynamical heterogeneities may emerge from the same structural mechanisms. We found that the formation of topologically-associating domains (TADs) is a key driver of chromatin motion heterogeneity. In particular, we demonstrated that the local degree of compaction of the TAD regulates the transition from a weakly compact, fluid state of chromatin to a more compact, gel state exhibiting anomalous diffusion and coherent motion. Our work provides a comprehensive study of chromosome dynamics and offers a unified view of chromatin motion allowing to interpret the wide variety of dynamical behaviors observed experimentally across different biological conditions.

Basement membrane and interstitial matrix components form separate matrices in heterokaryons of PYS-2 cells and fibroblasts

1993 ◽  
Vol 104 (1) ◽  
pp. 59-68
Author(s):  
P. Laurila ◽  
I. Leivo
Keyword(s):  
Basement Membrane ◽  
Matrix Protein ◽  
Spatial Organization ◽  
Gene Dosage ◽  
Parental Cell ◽  
Cell Nuclei ◽  
Fibronectin Matrix ◽  
Basement Membrane Protein ◽  
The Matrix

In order to gain further understanding of the spatial organization of interstitial and basement membrane matrices, we studied the expression of the interstitial matrix protein, fibronectin, and the basement membrane protein, laminin, in heterokaryons formed by the fusion of normal fibroblasts and teratocarcinoma-derived epithelial PYS-2 cells. These heterokaryons showed various distributions of the matrix proteins depending on the proportions of the different parental cell nuclei within the cytoplasm of the cell. Heterokaryons containing equal numbers of fibroblast and PYS-2 cell nuclei showed an abundant laminin matrix subcellularly and only minor amounts of fibronectin matrix at the periphery of the cells. Similar results were obtained in heterokaryons containing an excess of epithelial cell nuclei. In heterokaryons containing an excess of fibroblast nuclei, on the other hand, laminin matrix was reduced and a fibrillar fibronectin matrix was seen also on top of the cell body. The results suggest a gene dosage-type of effect on the expression of these proteins. Furthermore, extracellular laminin and fibronectin matrices did not codistribute around the heterokaryons but the two proteins were assembled into separate structures. The lack of codistribution of fibronectin and laminin matrices in heterokaryons suggests that the molecular interactions, which determine the assembly of basement membrane and interstitial matrices in these cells are highly type-specific. Similar mechanisms may also operate in the assembly of extracellular matrices in vivo.

scholarly journals Computational staining of pathology images to study tumor microenvironment in lung cancer

2019 ◽  
Author(s):  
Shidan Wang ◽  
Ruichen Rong ◽  
Donghan M. Yang ◽  
Ling Cai ◽  
Lin Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Microenvironment ◽  
Spatial Organization ◽  
Risk Group ◽  
Biological Pathways ◽  
The Cancer Genome Atlas ◽  
Analysis Tool ◽  
Cell Nuclei ◽  
Tumor Tissues ◽  
Different Types

ABSTRACTThe spatial organization of different types of cells in tumor tissues reveals important information about the tumor microenvironment (TME). In order to facilitate the study of cellular spatial organization and interactions, we developed a comprehensive nuclei segmentation and classification tool to characterize the TME from standard Hematoxylin and Eosin (H&E)-stained pathology images. This tool can computationally “stain” different types of cell nuclei in H&E pathology images to facilitate pathologists in analyzing the TME.A Mask Regional-Convolutional Neural Network (Mask-RCNN) model was developed to segment the nuclei of tumor, stromal, lymphocyte, macrophage, karyorrhexis and red blood cells in lung adenocarcinoma (ADC). Using this tool, we identified and classified cell nuclei and extracted 48 cell spatial organization-related features that characterize the TME. Using these features, we developed a prognostic model from the National Lung Screening Trial dataset, and independently validated the model in The Cancer Genome Atlas (TCGA) lung ADC dataset, in which the predicted high-risk group showed significantly worse survival than the low-risk group (pv= 0.001), with a hazard ratio of 2.23 [1.37-3.65] after adjusting for clinical variables. Furthermore, the image-derived TME features were significantly correlated with the gene expression of biological pathways. For example, transcription activation of both the T-cell receptor (TCR) and Programmed cell death protein 1 (PD1) pathways was positively correlated with the density of detected lymphocytes in tumor tissues, while expression of the extracellular matrix organization pathway was positively correlated with the density of stromal cells.This study developed a deep learning-based analysis tool to dissect the TME from tumor tissue images. Using this tool, we demonstrated that the spatial organization of different cell types is predictive of patient survival and associated with the gene expression of biological pathways. Although developed from the pathology images of lung ADC, this model can be adapted into other types of cancers.

scholarly journals Spatial Organization and Correlations of Cell Nuclei in Brain Tumors

PLoS ONE ◽  
2011 ◽  
Vol 6 (11) ◽  
pp. e27323 ◽  
Author(s):  
Yang Jiao ◽  
Hal Berman ◽  
Tim-Rasmus Kiehl ◽  
Salvatore Torquato
Keyword(s):  
Brain Tumors ◽  
Spatial Organization ◽  
Cell Nuclei

scholarly journals HMGB1 coordinates SASP-related chromatin folding and RNA homeostasis on the path to senescence

2019 ◽  
Author(s):  
Konstantinos Sofiadis ◽  
Milos Nikolic ◽  
Yulia Kargapolova ◽  
Natasa Josipovic ◽  
Anne Zirkel ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Spatial Organization ◽  
Rna Binding ◽  
Theory Approach ◽  
Cell Nuclei ◽  
Hmgb1 Protein ◽  
Physiological Importance ◽  
Genome Wide ◽  
Chromatin Folding ◽  
Bona Fide

AbstractSpatial organization and gene expression of mammalian chromosomes are maintained and regulated in conjunction with cell cycle progression. This is however disturbed once cells enter senescence and the highly abundant HMGB1 protein is depleted from senescent cell nuclei to act as an extracellular proinflammatory stimulus. Despite its physiological importance, we know little about the positioning of HMGB1 on chromatin or about its roles in the nucleus. To address this, we mapped HMGB1 binding genome-wide in different primary cells using a tailored protocol. We integrated ChIP-seq and Hi-C data with a graph theory approach to uncover HMGB1 demarcation of a subset of topologically-associating domains (TADs) that harbor genes required for paracrine senescence. Moreover, using sCLIP, knock-down and overexpression experiments, we now show that HMGB1 is abona fideRNA-binding protein (RBP) bound to senescence-relevant mRNAs and affecting splicing. HMGB1 also has an interactome rich in RBPs, many of which are implicated in senescence regulation. The mRNAs of many of these RBPs are directly bound by HMGB1 and concertedly regulate the availability of SASP-relevant transcripts. Our findings highlight a broader than hitherto assumed role for HMGB1. It coordinates chromatin folding and RNA homeostasis as part of a feedforward loop controlling both cell-autonomous and paracrine senescence inside and outside of cells.

scholarly journals Detection and Spatiotemporal analysis of in-vitro 3D migratory Triple-Negative Breast cancer cells

2021 ◽  
Author(s):  
Nikolaos M Dimitriou ◽  
Salvador Flores-Torres ◽  
Joseph Matthew Kinsella ◽  
Georgios D Mitsis
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Triple Negative Breast Cancer ◽  
Spatial Organization ◽  
Triple Negative ◽  
Migration And Invasion ◽  
Great Promise ◽  
Cell Nuclei ◽  
Wide Range

The invasion of cancer cells into the surrounding tissues is one of the hallmarks of cancer. However, a precise quantitative understanding of the spatiotemporal patterns of cancer cell migration and invasion still remains elusive. A promising approach to investigate these patterns are 3D cell cultures, which provide more realistic models of cancer growth compared to conventional 2D monolayers. Quantifying the spatial distribution of cells in these 3D cultures yields great promise for understanding the spatiotemporal progression of cancer. In the present study, we present an image processing and segmentation pipeline for the detection of 3D GFP-fluorescent Triple-Negative Breast Cancer cell nuclei, and we perform quantitative analysis of the formed spatial patterns and their temporal evolution. The performance of the proposed pipeline was evaluated using experimental 3D cell culture data, and was found to be comparable to manual segmentation, outperforming four alternative automated methods. The spatiotemporal statistical analysis of the detected distributions of nuclei revealed transient, non-random spatial distributions that consisted of clustered patterns across a wide range of neighbourhood distances, as well as dispersion for larger distances. Overall, the implementation of the proposed framework revealed the spatial organization of cellular nuclei with improved accuracy, providing insights into the 3 dimensional inter-cellular organization and its progression through time.

scholarly journals Locus-specific gene repositioning in prostate cancer

2016 ◽  
Vol 27 (2) ◽  
pp. 236-246 ◽  
Author(s):  
Marc Leshner ◽  
Michelle Devine ◽  
Gregory W. Roloff ◽  
Lawrence D. True ◽  
Tom Misteli ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Normal Tissue ◽  
Spatial Organization ◽  
Human Prostate ◽  
Specific Gene ◽  
Pathological Changes ◽  
Cell Nuclei ◽  
Prostate Hyperplasia ◽  
Interphase Cell ◽  
Prostate Disease

Genes occupy preferred spatial positions within interphase cell nuclei. However, positioning patterns are not an innate feature of a locus, and genes can alter their localization in response to physiological and pathological changes. Here we screen the radial positioning patterns of 40 genes in normal, hyperplasic, and malignant human prostate tissues. We find that the overall spatial organization of the genome in prostate tissue is largely conserved among individuals. We identify three genes whose nuclear positions are robustly altered in neoplastic prostate tissues. FLI1 and MMP9 position differently in prostate cancer than in normal tissue and prostate hyperplasia, whereas MMP2 is repositioned in both prostate cancer and hyperplasia. Our data point to locus-specific reorganization of the genome during prostate disease.

scholarly journals Topological demarcation by HMGB2 is disrupted early upon senescence entry across cell types and induces CTCF clustering

2017 ◽  
Author(s):  
Anne Zirkel ◽  
Milos Nikolic ◽  
Konstantinos Sofiadis ◽  
Jan-Philipp Mallm ◽  
Lilija Brant ◽  
...  
Keyword(s):  
Spatial Organization ◽  
Spatial Clustering ◽  
High Mobility ◽  
Super Resolution ◽  
Cell Types ◽  
Cell Nuclei ◽  
Genome Chromosome ◽  
Chromosome Conformation ◽  
Nuclear Factors ◽  
Stochastic Events

AbstractAgeing-relevant processes, like cellular senescence, are characterized by complex, often stochastic, events giving rise to heterogeneous cell populations. We hypothesized that entry into senescence of different primary human cells can be triggered by one early molecular event affecting the spatial organization of chromosomes. To test this, we combined whole-genome chromosome conformation capture, population and single-cell transcriptomics, super-resolution imaging, and functional analyses applied on proliferating and replicatively-senescent populations from three distinct human cell types. We found a number of genes involved in DNA conformation maintenance being suppressed upon senescence across cell types. Of these, the abundant high mobility group (HMG) B1 and B2 nuclear factors are quantitatively removed from cell nuclei before typical senescence markers appear, and mark a subset of topologically-associating domain (TAD) boundaries. Their loss coincides with obvious reorganization of chromatin interactions via the dramatic spatial clustering of CTCF foci. HMGB2 knock-down recapitulates this senescence-induced CTCF clustering, while also affecting insulation at TAD boundaries. We accordingly propose that HMGB-mediated deregulation of chromosome conformation constitutes a primer for the ensuing senescent program across cell types.

Climate Change and the Sustainable Small and Medium-Sized Enterprises

2021 ◽  
pp. 171-189
Author(s):  
Vanessa Gaffar ◽  
Tika Koeswandi
Keyword(s):  
Climate Change ◽  
Essential Role ◽  
Economic Resilience ◽  
Documentary Analysis ◽  
Financial Factor ◽  
National Economic ◽  
Green Practices ◽  
Development Goals ◽  
Key Driver ◽  
Two Sides

Small and medium-sized enterprises (SMEs) play an essential role as the key driver in national economic resilience. In developing countries, they contribute to most of the GDP every year. Like a coin with two sides, the rise of SME productivity accidentally caused the increase in global pollution. Now, the SMEs are urged to adjust and set the best strategies to encounter the circumstances. This chapter shares a broader perspective, literature studies, and documentary analysis on the definition and category of SMEs, the involvement of United Nations' Sustainable Development Goals (SDGs), green practices and strategies, and the issue of building sustainable SMEs in relation with climate change. It is also completed with some case studies in SMEs in Indonesia, Africa, United Kingdom, and many more. The chapters set the tone for the rest of the chapters examining the implications of the issues discussed for climate change and the sustainable financial factor.

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