Simulation of different three-dimensional polymer models of interphase chromosomes compared to experiments–an evaluation and review framework of the 3D genome organization

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.

Download Full-text

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

Nature Communications ◽

10.1038/s41467-019-13423-8 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 7

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.

Download Full-text

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 ◽

10.3390/biology10040272 ◽

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.

Download Full-text

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

Cell Death and Disease ◽

10.1038/s41419-021-04384-2 ◽

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.

Download Full-text

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

10.1101/2020.04.18.047738 ◽

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.

Download Full-text

Sci-Hi-C: a single-cell Hi-C method for mapping 3D genome organization in large number of single cells

10.1101/579573 ◽

2019 ◽

Cited By ~ 1

Author(s):

Vijay Ramani ◽

Xinxian Deng ◽

Ruolan Qiu ◽

Choli Lee ◽

Christine M Disteche ◽

...

Keyword(s):

Single Cell ◽

Genome Organization ◽

Single Cells ◽

Three Dimensional ◽

Population Based ◽

Order Structure ◽

Chromosome Conformation ◽

3D Genome ◽

A Cell ◽

Cell To Cell Variability

AbstractThe highly dynamic nature of chromosome conformation and three-dimensional (3D) genome organization leads to cell-to-cell variability in chromatin interactions within a cell population, even if the cells of the population appear to be functionally homogeneous. Hence, although Hi-C is a powerful tool for mapping 3D genome organization, this heterogeneity of chromosome higher order structure among individual cells limits the interpretive power of population based bulk Hi-C assays. Moreover, single-cell studies have the potential to enable the identification and characterization of rare cell populations or cell subtypes in a heterogeneous population. However, it may require surveying relatively large numbers of single cells to achieve statistically meaningful observations in single-cell studies. By applying combinatorial cellular indexing to chromosome conformation capture, we developed single-cell combinatorial indexed Hi-C (sci-Hi-C), a high throughput method that enables mapping chromatin interactomes in large number of single cells. We demonstrated the use of sci-Hi-C data to separate cells by karytoypic and cell-cycle state differences and to identify cellular variability in mammalian chromosomal conformation. Here, we provide a detailed description of method design and step-by-step working protocols for sci-Hi-C.

Download Full-text

Understanding 3D Genome Organization and Its Effect on Transcriptional Gene Regulation Under Environmental Stress in Plant: A Chromatin Perspective

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.774719 ◽

2021 ◽

Vol 9 ◽

Author(s):

Suresh Kumar ◽

Simardeep Kaur ◽

Karishma Seem ◽

Santosh Kumar ◽

Trilochan Mohapatra

Keyword(s):

Gene Expression ◽

Environmental Stress ◽

Genome Organization ◽

Regulation Of Gene Expression ◽

Three Dimensional ◽

Regulatory Elements ◽

Chromosome Conformation ◽

3D Genome ◽

Chromatin Architecture ◽

Capture Techniques

The genome of a eukaryotic organism is comprised of a supra-molecular complex of chromatin fibers and intricately folded three-dimensional (3D) structures. Chromosomal interactions and topological changes in response to the developmental and/or environmental stimuli affect gene expression. Chromatin architecture plays important roles in DNA replication, gene expression, and genome integrity. Higher-order chromatin organizations like chromosome territories (CTs), A/B compartments, topologically associating domains (TADs), and chromatin loops vary among cells, tissues, and species depending on the developmental stage and/or environmental conditions (4D genomics). Every chromosome occupies a separate territory in the interphase nucleus and forms the top layer of hierarchical structure (CTs) in most of the eukaryotes. While the A and B compartments are associated with active (euchromatic) and inactive (heterochromatic) chromatin, respectively, having well-defined genomic/epigenomic features, TADs are the structural units of chromatin. Chromatin architecture like TADs as well as the local interactions between promoter and regulatory elements correlates with the chromatin activity, which alters during environmental stresses due to relocalization of the architectural proteins. Moreover, chromatin looping brings the gene and regulatory elements in close proximity for interactions. The intricate relationship between nucleotide sequence and chromatin architecture requires a more comprehensive understanding to unravel the genome organization and genetic plasticity. During the last decade, advances in chromatin conformation capture techniques for unravelling 3D genome organizations have improved our understanding of genome biology. However, the recent advances, such as Hi-C and ChIA-PET, have substantially increased the resolution, throughput as well our interest in analysing genome organizations. The present review provides an overview of the historical and contemporary perspectives of chromosome conformation capture technologies, their applications in functional genomics, and the constraints in predicting 3D genome organization. We also discuss the future perspectives of understanding high-order chromatin organizations in deciphering transcriptional regulation of gene expression under environmental stress (4D genomics). These might help design the climate-smart crop to meet the ever-growing demands of food, feed, and fodder.

Download Full-text

Deciphering the Role of 3D Genome Organization in Breast Cancer Susceptibility

Frontiers in Genetics ◽

10.3389/fgene.2021.788318 ◽

2022 ◽

Vol 12 ◽

Author(s):

Brittany Baur ◽

Da-Inn Lee ◽

Jill Haag ◽

Deborah Chasman ◽

Michael Gould ◽

...

Keyword(s):

Breast Cancer ◽

Genome Organization ◽

Mammary Epithelial Cells ◽

Cancer Susceptibility ◽

Three Dimensional ◽

Breast Cancer Susceptibility ◽

Higher Order ◽

Mammary Epithelial ◽

3D Genome

Cancer risk by environmental exposure is modulated by an individual’s genetics and age at exposure. This age-specific period of susceptibility is referred to as the “Window of Susceptibility” (WOS). Rats have a similar WOS for developing breast cancer. A previous study in rat identified an age-specific long-range regulatory interaction for the cancer gene, Pappa, that is associated with breast cancer susceptibility. However, the global role of three-dimensional genome organization and downstream gene expression programs in the WOS is not known. Therefore, we generated Hi-C and RNA-seq data in rat mammary epithelial cells within and outside the WOS. To systematically identify higher-order changes in 3D genome organization, we developed NE-MVNMF that combines network enhancement followed by multitask non-negative matrix factorization. We examined three-dimensional genome organization dynamics at the level of individual loops as well as higher-order domains. Differential chromatin interactions tend to be associated with differentially up-regulated genes with the WOS and recapitulate several human SNP-gene interactions associated with breast cancer susceptibility. Our approach identified genomic blocks of regions with greater overall differences in contact count between the two time points when the cluster assignments change and identified genes and pathways implicated in early carcinogenesis and cancer treatment. Our results suggest that WOS-specific changes in 3D genome organization are linked to transcriptional changes that may influence susceptibility to breast cancer.

Download Full-text

Weak interactions in higher-order chromatin organization

Nucleic Acids Research ◽

10.1093/nar/gkaa261 ◽

2020 ◽

Vol 48 (9) ◽

pp. 4614-4626 ◽

Cited By ~ 5

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.

Download Full-text

Three-Dimensional Genome Organization and Virulence in Apicomplexan Parasites

Epigenetics Insights ◽

10.1177/2516865719879436 ◽

2019 ◽

Vol 12 ◽

pp. 251686571987943

Author(s):

Todd Lenz ◽

Karine G Le Roch

Keyword(s):

Gene Expression ◽

Genome Organization ◽

Three Dimensional ◽

Plasmodium Species ◽

Babesia Microti ◽

3 Dimensional ◽

Apicomplexan Parasites ◽

3D Genome ◽

3D Architecture ◽

Eukaryotic Organisms

Mounting evidence supports the idea that epigenetic, and the overall 3-dimensional (3D) architecture of the genome, plays an important role in gene expression for eukaryotic organisms. We recently used Hi-C methodologies to generate and compare the 3D genome of 7 different apicomplexan parasites, including several pathogenic and less pathogenic malaria parasites as well as related human parasites Babesia microti and Toxoplasma gondii. Our goal was to understand the possible relationship between genome organization, gene expression, and pathogenicity of these infectious agents. Collectively, our results demonstrate that spatial genome organization in most Plasmodium species is constrained by the colocalization of virulence genes that are unique in their effect on chromosome folding, indicating a link between genome organization and gene expression in more virulent pathogens.

Download Full-text