scholarly journals Weak interactions in higher-order chromatin organization

2020 ◽  
Vol 48 (9) ◽  
pp. 4614-4626 ◽  
Author(s):  
Omar L Kantidze ◽  
Sergey V Razin
Keyword(s):  
Genome Organization ◽  
Electrostatic Interactions ◽  
Molecular Mechanisms ◽  
Weak Interactions ◽  
Three Dimensional ◽  
Dna Supercoiling ◽  
3D Genome ◽  
Protein Dna Interactions ◽  
Spatial Genome Organization ◽  
Hierarchical Folding

Abstract The detailed principles of the hierarchical folding of eukaryotic chromosomes have been revealed during the last two decades. Along with structures composing three-dimensional (3D) genome organization (chromatin compartments, topologically associating domains, chromatin loops, etc.), the molecular mechanisms that are involved in their establishment and maintenance have been characterized. Generally, protein–protein and protein–DNA interactions underlie the spatial genome organization in eukaryotes. However, it is becoming increasingly evident that weak interactions, which exist in biological systems, also contribute to the 3D genome. Here, we provide a snapshot of our current understanding of the role of the weak interactions in the establishment and maintenance of the 3D genome organization. We discuss how weak biological forces, such as entropic forces operating in crowded solutions, electrostatic interactions of the biomolecules, liquid-liquid phase separation, DNA supercoiling, and RNA environment participate in chromosome segregation into structural and functional units and drive intranuclear functional compartmentalization.

scholarly journals 3D genome organization during lymphocyte development and activation

2019 ◽  
Vol 19 (2) ◽  
pp. 71-82 ◽  
Author(s):  
Anne van Schoonhoven ◽  
Danny Huylebroeck ◽  
Rudi W Hendriks ◽  
Ralph Stadhouders
Keyword(s):  
Genome Organization ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Three Dimensional ◽  
Lymphocyte Development ◽  
Control Of Gene Expression ◽  
3D Genome ◽  
Wide Range ◽  
3D Architecture

Abstract Chromosomes have a complex three-dimensional (3D) architecture comprising A/B compartments, topologically associating domains and promoter–enhancer interactions. At all these levels, the 3D genome has functional consequences for gene transcription and therefore for cellular identity. The development and activation of lymphocytes involves strict control of gene expression by transcription factors (TFs) operating in a three-dimensionally organized chromatin landscape. As lymphocytes are indispensable for tissue homeostasis and pathogen defense, and aberrant lymphocyte activity is involved in a wide range of human morbidities, acquiring an in-depth understanding of the molecular mechanisms that control lymphocyte identity is highly relevant. Here we review current knowledge of the interplay between 3D genome organization and transcriptional control during B and T lymphocyte development and antigen-dependent activation, placing special emphasis on the role of TFs.

scholarly journals At the Crossroad of Gene Regulation and Genome Organization: Potential Roles for ATP-Dependent Chromatin Remodelers in the Regulation of CTCF-Mediated 3D Architecture

Biology ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 272
Author(s):  
Aktan Alpsoy ◽  
Surbhi Sood ◽  
Emily C. Dykhuizen
Keyword(s):  
Genome Organization ◽  
Three Dimensional ◽  
Chromatin Remodelers ◽  
3D Genome ◽  
Quiescent Cells ◽  
Damage Repair ◽  
Architectural Proteins ◽  
3D Architecture ◽  
Specific Factors ◽  
Hierarchical Folding

In higher order organisms, the genome is assembled into a protein-dense structure called chromatin. Chromatin is spatially organized in the nucleus through hierarchical folding, which is tightly regulated both in cycling cells and quiescent cells. Assembly and folding are not one-time events in a cell’s lifetime; rather, they are subject to dynamic shifts to allow changes in transcription, DNA replication, or DNA damage repair. Chromatin is regulated at many levels, and recent tools have permitted the elucidation of specific factors involved in the maintenance and regulation of the three-dimensional (3D) genome organization. In this review/perspective, we aim to cover the potential, but relatively unelucidated, crosstalk between 3D genome architecture and the ATP-dependent chromatin remodelers with a specific focus on how the architectural proteins CTCF and cohesin are regulated by chromatin remodeling.

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.

scholarly journals HP1 drives de novo 3D genome reorganization in early Drosophila embryos

Nature ◽  
2021 ◽  
Author(s):  
Fides Zenk ◽  
Yinxiu Zhan ◽  
Pavel Kos ◽  
Eva Löser ◽  
Nazerke Atinbayeva ◽  
...  
Keyword(s):  
Genome Organization ◽  
Molecular Mechanisms ◽  
High Throughput Sequencing ◽  
De Novo ◽  
Early Embryo ◽  
Heterochromatin Protein ◽  
Chromosome Conformation ◽  
3D Genome ◽  
Genome Reorganization

AbstractFundamental features of 3D genome organization are established de novo in the early embryo, including clustering of pericentromeric regions, the folding of chromosome arms and the segregation of chromosomes into active (A-) and inactive (B-) compartments. However, the molecular mechanisms that drive de novo organization remain unknown1,2. Here, by combining chromosome conformation capture (Hi-C), chromatin immunoprecipitation with high-throughput sequencing (ChIP–seq), 3D DNA fluorescence in situ hybridization (3D DNA FISH) and polymer simulations, we show that heterochromatin protein 1a (HP1a) is essential for de novo 3D genome organization during Drosophila early development. The binding of HP1a at pericentromeric heterochromatin is required to establish clustering of pericentromeric regions. Moreover, HP1a binding within chromosome arms is responsible for overall chromosome folding and has an important role in the formation of B-compartment regions. However, depletion of HP1a does not affect the A-compartment, which suggests that a different molecular mechanism segregates active chromosome regions. Our work identifies HP1a as an epigenetic regulator that is involved in establishing the global structure of the genome in the early embryo.

scholarly journals Technologies to study spatial genome organization: beyond 3C

2019 ◽  
Author(s):  
Nadine Übelmesser ◽  
Argyris Papantonis
Keyword(s):  
Genome Organization ◽  
Nuclear Organization ◽  
Three Dimensional ◽  
Nuclear Space ◽  
Chromosome Conformation ◽  
Novel Variants ◽  
Cell Processes ◽  
Systematic Biases ◽  
And Function ◽  
Spatial Genome Organization

Abstract The way that chromatin is organized in three-dimensional nuclear space is now acknowledged as a factor critical for the major cell processes, like transcription, replication and cell division. Researchers have been armed with new molecular and imaging technologies to study this structure-to-function link of genomes, spearheaded by the introduction of the ‘chromosome conformation capture’ technology more than a decade ago. However, this technology is not without shortcomings, and novel variants and orthogonal approaches are being developed to overcome these. As a result, the field of nuclear organization is constantly fueled by methods of increasing resolution and/or throughput that strive to eliminate systematic biases and increase precision. In this review, we attempt to highlight the most recent advances in technology that promise to provide novel insights on how chromosomes fold and function.

scholarly journals Identification and analysis of consensus RNA motifs binding to the genome regulator CTCF

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Shuzhen Kuang ◽  
Liangjiang Wang
Keyword(s):  
Genome Organization ◽  
Molecular Mechanisms ◽  
Short Term Memory ◽  
Consensus Sequence ◽  
Ctcf Binding ◽  
Specific Sequence ◽  
3D Genome ◽  
Rna Transcripts ◽  
Memory Network ◽  
Rna Motif

Abstract CCCTC-binding factor (CTCF) is a key regulator of 3D genome organization and gene expression. Recent studies suggest that RNA transcripts, mostly long non-coding RNAs (lncRNAs), can serve as locus-specific factors to bind and recruit CTCF to the chromatin. However, it remains unclear whether specific sequence patterns are shared by the CTCF-binding RNA sites, and no RNA motif has been reported so far for CTCF binding. In this study, we have developed DeepLncCTCF, a new deep learning model based on a convolutional neural network and a bidirectional long short-term memory network, to discover the RNA recognition patterns of CTCF and identify candidate lncRNAs binding to CTCF. When evaluated on two different datasets, human U2OS dataset and mouse ESC dataset, DeepLncCTCF was shown to be able to accurately predict CTCF-binding RNA sites from nucleotide sequence. By examining the sequence features learned by DeepLncCTCF, we discovered a novel RNA motif with the consensus sequence, AGAUNGGA, for potential CTCF binding in humans. Furthermore, the applicability of DeepLncCTCF was demonstrated by identifying nearly 5000 candidate lncRNAs that might bind to CTCF in the nucleus. Our results provide useful information for understanding the molecular mechanisms of CTCF function in 3D genome organization.

scholarly journals Heterogeneity and Intrinsic Variation in Spatial Genome Organization

2017 ◽  
Author(s):  
Elizabeth H. Finn ◽  
Gianluca Pegoraro ◽  
Hugo B. Brandão ◽  
Anne-Laure Valton ◽  
Marlies E. Oomen ◽  
...  
Keyword(s):  
Genome Organization ◽  
Single Cells ◽  
Human Fibroblasts ◽  
Intrinsic Variability ◽  
Cell Level ◽  
3D Genome ◽  
3D Space ◽  
A Cell ◽  
Spatial Genome Organization ◽  
Independent Behavior

AbstractThe genome is hierarchically organized in 3D space and its architecture is altered in differentiation, development and disease. Some of the general principles that determine global 3D genome organization have been established. However, the extent and nature of cell-to-cell and cell-intrinsic variability in genome architecture are poorly characterized. Here, we systematically probe the heterogeneity in genome organization in human fibroblasts by combining high-resolution Hi-C datasets and high-throughput genome imaging. Optical mapping of several hundred genome interaction pairs at the single cell level demonstrates low steady-state frequencies of colocalization in the population and independent behavior of individual alleles in single nuclei. Association frequencies are determined by genomic distance, higher-order chromatin architecture and chromatin environment. These observations reveal extensive variability and heterogeneity in genome organization at the level of single cells and alleles and they demonstrate the coexistence of a broad spectrum of chromatin and genome conformations in a cell population.

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 Defective chromatin architectures in embryonic stem cells derived from somatic cell nuclear transfer impair their differentiation potentials

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Dan-Ya Wu ◽  
Xinxin Li ◽  
Qiao-Ran Sun ◽  
Cheng-Li Dou ◽  
Tian Xu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Somatic Cell ◽  
Genome Organization ◽  
Nuclear Transfer ◽  
Three Dimensional ◽  
Embryonic Stem ◽  
Chromatin Accessibility ◽  
Differentiation Potential ◽  
3D Genome

AbstractNuclear transfer embryonic stem cells (ntESCs) hold enormous promise for individual-specific regenerative medicine. However, the chromatin states of ntESCs remain poorly characterized. In this study, we employed ATAC-seq and Hi-C techniques to explore the chromatin accessibility and three-dimensional (3D) genome organization of ntESCs. The results show that the chromatin accessibility and genome structures of somatic cells are re-arranged to ESC-like states overall in ntESCs, including compartments, topologically associating domains (TADs) and chromatin loops. However, compared to fertilized ESCs (fESCs), ntESCs show some abnormal openness and structures that have not been reprogrammed completely, which impair the differentiation potential of ntESCs. The histone modification H3K9me3 may be involved in abnormal structures in ntESCs, including incorrect compartment switches and incomplete TAD rebuilding. Moreover, ntESCs and iPSCs show high similarity in 3D genome structures, while a few differences are detected due to different somatic cell origins and reprogramming mechanisms. Through systematic analyses, our study provides a global view of chromatin accessibility and 3D genome organization in ntESCs, which can further facilitate the understanding of the similarities and differences between ntESCs and fESCs.

scholarly journals Three-dimensional Genome Organization Maps in Normal Haematopoietic Stem Cells and Acute Myeloid Leukemia

2020 ◽  
Author(s):  
Benny Wang ◽  
Lingshi Kong ◽  
Deepak Babu ◽  
Ruchi Choudhary ◽  
Winnie Fam ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Genome Organization ◽  
Myeloid Leukemia ◽  
Three Dimensional ◽  
Haematopoietic Stem Cells ◽  
3D Genome ◽  
Oncogene Expression ◽  
Super Enhancer ◽  
Acute Myeloid

AbstractAcute Myeloid Leukemia (AML) is a highly lethal blood cancer arising due to aberrant differentiation of haematopoietic stem cells. MEIS1 and HOXA9 regulate stemness-related transcriptional programs in normal haematopoietic stem cells and AML. Here we obtained 3D genome organization maps in the CD34+ haematopoietic stem cells from 3 healthy individuals and 3 individuals with AML. The MEIS1 oncogenic transcription factor is regulated by a Frequently Interacting Region (FIRE). This FIRE is present in normal bone marrow samples, and an AML sample with high MEIS1 levels. However, it is absent in two AML samples that show low MEIS1 levels. CRISPR excision of the FIRE led to loss of MEIS1 and reduced cell growth. Moreover, MEIS1 can bind to the promoter of HOXA9, and HOXA9 can also auto-regulate by binding to its own promoter as well as an Acute Myeloid Leukemia-specific super-enhancer that interacts with the HOXA9 promoter via chromatin interactions.SignificanceMany oncogenes, such as MEIS1 and HOXA9, are overexpressed in some but not all cancers. We identified two key epigenetic mechanisms underlying this heterogeneity in oncogene expression in Acute Myeloid Leukemia. This mechanism could be potentially exploited to utilize epigenetic inhibitors to specifically target oncogene expression in cancer.

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