Weak interactions in higher-order chromatin organization. Kantidze Omar L,Razin Sergey V Nucleic acids research 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. 10.1093/nar/gkaa261
    The 3D Genome as a Target for Anticancer Therapy. Kantidze Omar L,Gurova Katerina V,Studitsky Vasily M,Razin Sergey V Trends in molecular medicine The role of 3D genome organization in the precise regulation of gene expression is well established. Accordingly, the mechanistic connections between 3D genome alterations and disease development are becoming increasingly apparent. This opinion article provides a snapshot of our current understanding of the 3D genome alterations associated with cancers. We discuss potential connections of the 3D genome and cancer transcriptional addiction phenomenon as well as molecular mechanisms of action of 3D genome-disrupting drugs. Finally, we highlight issues and perspectives raised by the discovery of the first pharmaceutical strongly affecting 3D genome organization. 10.1016/j.molmed.2019.09.011
    The interdependence of gene-regulatory elements and the 3D genome. Vermunt Marit W,Zhang Di,Blobel Gerd A The Journal of cell biology Imaging studies, high-resolution chromatin conformation maps, and genome-wide occupancy data of architectural proteins have revealed that genome topology is tightly intertwined with gene expression. Cross-talk between gene-regulatory elements is often organized within insulated neighborhoods, and regulatory cues that induce transcriptional changes can reshape chromatin folding patterns and gene positioning within the nucleus. The cause-consequence relationship of genome architecture and gene expression is intricate, and its molecular mechanisms are under intense investigation. Here, we review the interdependency of transcription and genome organization with emphasis on enhancer-promoter contacts in gene regulation. 10.1083/jcb.201809040
    The Birth of the 3D Genome during Early Embryonic Development. Hug Clemens B,Vaquerizas Juan M Trends in genetics : TIG The 3D structure of chromatin in the nucleus is important for the regulation of gene expression and the correct deployment of developmental programs. The differentiation of germ cells and early embryonic development (when the zygotic genome is activated and transcription is taking place for the first time) are accompanied by dramatic changes in gene expression and the epigenetic landscape. Recent studies used Hi-C to investigate the 3D chromatin organization during these developmental transitions, uncovering remarkable remodeling of the 3D genome. Here, we highlight the changes described so far and discuss some of the implications that these findings have for our understanding of the mechanisms and functionality of 3D chromatin architecture. 10.1016/j.tig.2018.09.002
    Computational methods for analyzing genome-wide chromosome conformation capture data. Nicoletti Chiara,Forcato Mattia,Bicciato Silvio Current opinion in biotechnology In all organisms, chromatin is packed to fulfil structural constraints and functional requirements. The hierarchical model of chromatin organization in the 3D nuclear space encompasses different topologies at diverse scale lengths, with chromosomes occupying distinct volumes, further organized in compartments, inside which the chromatin fibers fold into large domains and short-range loops. In the recent years, the combination of chromosome conformation capture (3C) techniques and high-throughput sequencing allowed probing chromatin spatial organization at the whole genome-scale. 3C-based methods produce enormous amounts of genomic data that are analyzed using ad-hoc computational procedures. Here, we review the common pipelines and methods for the analysis of genome-wide chromosome conformation capture data, highlighting recent developments in key steps for the identification of chromatin structures. 10.1016/j.copbio.2018.01.023
    3D modelling of gene expression patterns. Streicher J,Müller G B Trends in biotechnology The current genome-sequencing projects provide "word indices" of the book of life. A central post-genomic question will be how these words are three-dimensionally deployed in the generation of organism form. Gene expression studies of developing organisms contribute an increasing wealth of snapshot data on the activation of individual genes at selected locations and single moments in the developmental process. However, a comprehensive understanding of the dynamic activation of multiple genes and their functional role in controlling the 3D processes of collective cell behaviour, pattern formation and morphogenesis, requires special tools for a systematic description of spatio-temporal patterns of gene activation and the ensuing phenotypic effects. This article concentrates on new, computer-based tools for the 3D analysis of gene expression patterns in embryonic development and their use for the systematic establishment of comprehensive gene expression maps. 10.1016/s0167-7799(00)01571-7
    Transcription Factors and DNA Play Hide and Seek. Suter David M Trends in cell biology Transcription factors (TFs) bind to specific DNA motifs to regulate the expression of target genes. To reach their binding sites, TFs diffuse in 3D and perform local motions such as 1D sliding, hopping, or intersegmental transfer. TF-DNA interactions depend on multiple parameters, such as the chromatin environment, TF partitioning into distinct subcellular regions, and cooperativity with other DNA-binding proteins. In this review, how current understanding of the search process has initially been shaped by prokaryotic studies is discussed, as well as what is known about the parameters regulating TF search efficiency in the context of the complex eukaryotic chromatin landscape. 10.1016/j.tcb.2020.03.003
    Software tools for visualizing Hi-C data. Yardımcı Galip Gürkan,Noble William Stafford Genome biology High-throughput assays for measuring the three-dimensional (3D) configuration of DNA have provided unprecedented insights into the relationship between DNA 3D configuration and function. Data interpretation from assays such as ChIA-PET and Hi-C is challenging because the data is large and cannot be easily rendered using standard genome browsers. An effective Hi-C visualization tool must provide several visualization modes and be capable of viewing the data in conjunction with existing, complementary data. We review five software tools that do not require programming expertise. We summarize their complementary functionalities, and highlight which tool is best equipped for specific tasks. 10.1186/s13059-017-1161-y
    Nucleolus: A Central Hub for Nuclear Functions. Iarovaia Olga V,Minina Elizaveta P,Sheval Eugene V,Onichtchouk Daria,Dokudovskaya Svetlana,Razin Sergey V,Vassetzky Yegor S Trends in cell biology The nucleolus is the largest and most studied nuclear body, but its role in nuclear function is far from being comprehensively understood. Much work on the nucleolus has focused on its role in regulating RNA polymerase I (RNA Pol I) transcription and ribosome biogenesis; however, emerging evidence points to the nucleolus as an organizing hub for many nuclear functions, accomplished via the shuttling of proteins and nucleic acids between the nucleolus and nucleoplasm. Here, we discuss the cellular mechanisms affected by shuttling of nucleolar components, including the 3D organization of the genome, stress response, DNA repair and recombination, transcription regulation, telomere maintenance, and other essential cellular functions. 10.1016/j.tcb.2019.04.003
    Long-range enhancer-promoter contacts in gene expression control. Schoenfelder Stefan,Fraser Peter Nature reviews. Genetics Spatiotemporal gene expression programmes are orchestrated by transcriptional enhancers, which are key regulatory DNA elements that engage in physical contacts with their target-gene promoters, often bridging considerable genomic distances. Recent progress in genomics, genome editing and microscopy methodologies have enabled the genome-wide mapping of enhancer-promoter contacts and their functional dissection. In this Review, we discuss novel concepts on how enhancer-promoter interactions are established and maintained, how the 3D architecture of mammalian genomes both facilitates and constrains enhancer-promoter contacts, and the role they play in gene expression control during normal development and disease. 10.1038/s41576-019-0128-0
    Understanding the molecular machinery of genetics through 3D structures. Laskowski Roman A,Thornton Janet M Nature reviews. Genetics Detailed knowledge of the three-dimensional structures of biological molecules has had an enormous impact on all areas of biological science, including genetics, as structure can reveal the fine details of how molecules perform their biological functions. Here we consider how changes in protein sequence affect the corresponding 3D structure, and describe how structural information about proteins, DNA and chromatin has shed light on gene regulatory mechanisms and the storage and transmission of epigenetic information. Finally, we describe how structure determination is benefiting from the high-throughput technologies of the worldwide structural genomics projects. 10.1038/nrg2273
    Histone Variants and Histone Modifications in Neurogenesis. Zhang Mengtian,Zhao Jinyue,Lv Yuqing,Wang Wenwen,Feng Chao,Zou Wenzheng,Su Libo,Jiao Jianwei Trends in cell biology During embryonic brain development, neurogenesis requires the orchestration of gene expression to regulate neural stem cell (NSC) fate specification. Epigenetic regulation with specific emphasis on the modes of histone variants and histone post-translational modifications are involved in interactive gene regulation of central nervous system (CNS) development. Here, we provide a broad overview of the regulatory system of histone variants and histone modifications that have been linked to neurogenesis and diseases. We also review the crosstalk between different histone modifications and discuss how the 3D genome affects cell fate dynamics during brain development. Understanding the mechanisms of epigenetic regulation in neurogenesis has shifted the paradigm from single gene regulation to synergistic interactions to ensure healthy embryonic neurogenesis. 10.1016/j.tcb.2020.09.003
    Emerging themes in cohesin cancer biology. Waldman Todd Nature reviews. Cancer Mutations of the cohesin complex in human cancer were first discovered ~10 years ago. Since then, researchers worldwide have demonstrated that cohesin is among the most commonly mutated protein complexes in cancer. Inactivating mutations in genes encoding cohesin subunits are common in bladder cancers, paediatric sarcomas, leukaemias, brain tumours and other cancer types. Also in those 10 years, the prevailing view of the functions of cohesin in cell biology has undergone a revolutionary transformation. Initially, the predominant view of cohesin was as a ring that encircled and cohered replicated chromosomes until its cleavage triggered the metaphase-to-anaphase transition. As such, early studies focused on the role of tumour-derived cohesin mutations in the fidelity of chromosome segregation and aneuploidy. However, over the past 5 years the cohesin field has shifted dramatically, and research now focuses on the primary role of cohesin in generating, maintaining and regulating the intra-chromosomal DNA looping events that modulate 3D genome organization and gene expression. This Review focuses on recent discoveries in the cohesin field that provide insight into the role of cohesin inactivation in cancer pathogenesis, and opportunities for exploiting these findings for the clinical benefit of patients with cohesin-mutant cancers. 10.1038/s41568-020-0270-1
    Epigenome in Early Mammalian Development: Inheritance, Reprogramming and Establishment. Xu Qianhua,Xie Wei Trends in cell biology Drastic epigenetic reprogramming takes place during preimplantation development, leading to the conversion of terminally differentiated gametes to a totipotent embryo. Deficiencies in remodeling of the epigenomes can cause severe developmental defects, including embryonic lethality. However, how chromatin modifications and chromatin organization are reprogrammed upon fertilization in mammals has long remained elusive. Here, we review recent progress in understanding how the epigenome is dynamically regulated during early mammalian development. The latest studies, including many from genome-wide perspectives, have revealed unusual principles of reprogramming for histone modifications, chromatin accessibility, and 3D chromatin architecture. These advances have shed light on the regulatory network controlling the earliest development and maternal-zygotic transition. 10.1016/j.tcb.2017.10.008
    Long noncoding RNAs: an emerging link between gene regulation and nuclear organization. Quinodoz Sofia,Guttman Mitchell Trends in cell biology Mammalian genomes encode thousands of long noncoding RNAs (lncRNAs) that play important roles in diverse biological processes. As a class, lncRNAs are generally enriched in the nucleus and, specifically, within the chromatin-associated fraction. Consistent with their localization, many lncRNAs have been implicated in the regulation of gene expression and in shaping 3D nuclear organization. In this review, we discuss the evidence that many nuclear-retained lncRNAs can interact with various chromatin regulatory proteins and recruit them to specific sites on DNA to regulate gene expression. Furthermore, we discuss the role of specific lncRNAs in shaping nuclear organization and their emerging mechanisms. Based on these examples, we propose a model that explains how lncRNAs may shape aspects of nuclear organization to regulate gene expression. 10.1016/j.tcb.2014.08.009
    Absence of a simple code: how transcription factors read the genome. Slattery Matthew,Zhou Tianyin,Yang Lin,Dantas Machado Ana Carolina,Gordân Raluca,Rohs Remo Trends in biochemical sciences Transcription factors (TFs) influence cell fate by interpreting the regulatory DNA within a genome. TFs recognize DNA in a specific manner; the mechanisms underlying this specificity have been identified for many TFs based on 3D structures of protein-DNA complexes. More recently, structural views have been complemented with data from high-throughput in vitro and in vivo explorations of the DNA-binding preferences of many TFs. Together, these approaches have greatly expanded our understanding of TF-DNA interactions. However, the mechanisms by which TFs select in vivo binding sites and alter gene expression remain unclear. Recent work has highlighted the many variables that influence TF-DNA binding, while demonstrating that a biophysical understanding of these many factors will be central to understanding TF function. 10.1016/j.tibs.2014.07.002
    Spatial genome organization and cognition. Rajarajan Prashanth,Gil Sergio Espeso,Brennand Kristen J,Akbarian Schahram Nature reviews. Neuroscience Nonrandom chromosomal conformations, including promoter-enhancer loopings that bypass kilobases or megabases of linear genome, provide a crucial layer of transcriptional regulation and move vast amounts of non-coding sequence into the physical proximity of genes that are important for neurodevelopment, cognition and behaviour. Activity-regulated changes in the neuronal '3D genome' could govern transcriptional mechanisms associated with learning and plasticity, and loop-bound intergenic and intronic non-coding sequences have been implicated in psychiatric and adult-onset neurodegenerative disease. Recent studies have begun to clarify the roles of spatial genome organization in normal and abnormal cognition. 10.1038/nrn.2016.124
    The epigenomics of sarcoma. Nacev Benjamin A,Jones Kevin B,Intlekofer Andrew M,Yu Jamie S E,Allis C David,Tap William D,Ladanyi Marc,Nielsen Torsten O Nature reviews. Cancer Epigenetic regulation is critical to physiological control of development, cell fate, cell proliferation, genomic integrity and, fundamentally, transcriptional regulation. This epigenetic control occurs at multiple levels including through DNA methylation, histone modification, nucleosome remodelling and modulation of the 3D chromatin structure. Alterations in genes that encode chromatin regulators are common among mesenchymal neoplasms, a collection of more than 160 tumour types including over 60 malignant variants (sarcomas) that have unique and varied genetic, biological and clinical characteristics. Herein, we review those sarcomas in which chromatin pathway alterations drive disease biology. Specifically, we emphasize examples of dysregulation of each level of epigenetic control though mechanisms that include alterations in metabolic enzymes that regulate DNA methylation and histone post-translational modifications, mutations in histone genes, subunit loss or fusions in chromatin remodelling and modifying complexes, and disruption of higher-order chromatin structure. Epigenetic mechanisms of tumorigenesis have been implicated in mesenchymal tumours ranging from chondroblastoma and giant cell tumour of bone to chondrosarcoma, malignant peripheral nerve sheath tumour, synovial sarcoma, epithelioid sarcoma and Ewing sarcoma - all diseases that present in a younger patient population than most cancers. Finally, we review current and potential future approaches for the development of sarcoma therapies based on this emerging understanding of chromatin dysregulation. 10.1038/s41568-020-0288-4
    Emerging concepts of epigenetic dysregulation in hematological malignancies. Ntziachristos Panagiotis,Abdel-Wahab Omar,Aifantis Iannis Nature immunology The past decade brought a revolution in understanding of the structure, topology and disease-inducing lesions of RNA and DNA, fueled by unprecedented progress in next-generation sequencing. This technological revolution has also affected understanding of the epigenome and has provided unique opportunities for the analysis of DNA and histone modifications, as well as the first map of the non-protein-coding genome and three-dimensional (3D) chromosomal interactions. Overall, these advances have facilitated studies that combine genetic, transcriptomics and epigenomics data to address a wide range of issues ranging from understanding the role of the epigenome in development to targeting the transcription of noncoding genes in human cancer. Here we describe recent insights into epigenetic dysregulation characteristic of the malignant differentiation of blood stem cells based on studies of alterations that affect epigenetic complexes, enhancers, chromatin, long noncoding RNAs (lncRNAs), RNA splicing, nuclear topology and the 3D conformation of chromatin. 10.1038/ni.3517
    Genome organization in immune cells: unique challenges. Johanson Timothy M,Chan Wing Fuk,Keenan Christine R,Allan Rhys S Nature reviews. Immunology Each type of cell in the immune system performs critical functions to protect the body and maintain health. In order to fulfil these roles some immune cells rely on unique processes, including antigen receptor loci recombination, clonal expansion or the contortion of their nuclei. In turn, each of these processes relies on, or poses unique challenges to, a genome organized in three dimensions. Here, we explore the current understanding of the importance of 3D genome organization in the function and development of a healthy immune system. 10.1038/s41577-019-0155-2
    Challenges and guidelines toward 4D nucleome data and model standards. Marti-Renom Marc A,Almouzni Genevieve,Bickmore Wendy A,Bystricky Kerstin,Cavalli Giacomo,Fraser Peter,Gasser Susan M,Giorgetti Luca,Heard Edith,Nicodemi Mario,Nollmann Marcelo,Orozco Modesto,Pombo Ana,Torres-Padilla Maria-Elena Nature genetics Due to recent advances in experimental and theoretical approaches, the dynamic three-dimensional organization (3D) of the nucleus has become a very active area of research in life sciences. We now understand that the linear genome is folded in ways that may modulate how genes are expressed during the basic functioning of cells. Importantly, it is now possible to build 3D models of how the genome folds within the nucleus and changes over time (4D). Because genome folding influences its function, this opens exciting new possibilities to broaden our understanding of the mechanisms that determine cell fate. However, the rapid evolution of methods and the increasing complexity of data can result in ambiguity and reproducibility challenges, which may hamper the progress of this field. Here, we describe such challenges ahead and provide guidelines to think about strategies for shared standardized validation of experimental 4D nucleome data sets and models. 10.1038/s41588-018-0236-3
    Coaching from the sidelines: the nuclear periphery in genome regulation. Buchwalter Abigail,Kaneshiro Jeanae M,Hetzer Martin W Nature reviews. Genetics The genome is packaged and organized nonrandomly within the 3D space of the nucleus to promote efficient gene expression and to faithfully maintain silencing of heterochromatin. The genome is enclosed within the nucleus by the nuclear envelope membrane, which contains a set of proteins that actively participate in chromatin organization and gene regulation. Technological advances are providing views of genome organization at unprecedented resolution and are beginning to reveal the ways that cells co-opt the structures of the nuclear periphery for nuclear organization and gene regulation. These genome regulatory roles of proteins of the nuclear periphery have important influences on development, disease and ageing. 10.1038/s41576-018-0063-5
    Enhancer function: mechanistic and genome-wide insights come together. Plank Jennifer L,Dean Ann Molecular cell Enhancers establish spatial or temporal patterns of gene expression that are critical for development, yet our understanding of how these DNA cis-regulatory elements function from a distance to increase transcription of their target genes and shape the cellular transcriptome has been gleaned primarily from studies of individual genes or gene families. High-throughput sequencing studies place enhancer-gene interactions within the 3D context of chromosome folding, inviting a new look at enhancer function and stimulating provocative new questions. Here, we integrate these whole-genome studies with recent mechanistic studies to illuminate how enhancers physically interact with target genes, how enhancer activity is regulated during development, and the role of noncoding RNAs transcribed from enhancers in their function. 10.1016/j.molcel.2014.06.015
    The X chromosome in space. Jégu Teddy,Aeby Eric,Lee Jeannie T Nature reviews. Genetics Extensive 3D folding is required to package a genome into the tiny nuclear space, and this packaging must be compatible with proper gene expression. Thus, in the well-hierarchized nucleus, chromosomes occupy discrete territories and adopt specific 3D organizational structures that facilitate interactions between regulatory elements for gene expression. The mammalian X chromosome exemplifies this structure-function relationship. Recent studies have shown that, upon X-chromosome inactivation, active and inactive X chromosomes localize to different subnuclear positions and adopt distinct chromosomal architectures that reflect their activity states. Here, we review the roles of long non-coding RNAs, chromosomal organizational structures and the subnuclear localization of chromosomes as they relate to X-linked gene expression. 10.1038/nrg.2017.17
    "Cat's Cradling" the 3D Genome by the Act of LncRNA Transcription. Melé Marta,Rinn John L Molecular cell There is growing evidence that transcription and nuclear organization are tightly linked. Yet, whether transcription of thousands of long noncoding RNAs (lncRNAs) could play a role in this packaging process remains elusive. Although some lncRNAs have been found to have clear roles in nuclear architecture (e.g., FIRRE, NEAT1, XIST, and others), the vast majority remain poorly understood. In this Perspective, we highlight how the act of transcription can affect nuclear architecture. We synthesize several recent findings into a proposed model where the transcription of lncRNAs can serve as guide-posts for shaping genome organization. This model is similar to the game "cat's cradle," where the shape of a string is successively changed by opening up new sites for finger placement. Analogously, transcription of lncRNAs could serve as "grip holds" for nuclear proteins to pull the genome into new positions. This model could explain general lncRNA properties such as low abundance and tissue specificity. Overall, we propose a general framework for how the act of lncRNA transcription could play a role in organizing the 3D genome. 10.1016/j.molcel.2016.05.011
    The 3D genome in transcriptional regulation and pluripotency. Gorkin David U,Leung Danny,Ren Bing Cell stem cell It can be convenient to think of the genome as simply a string of nucleotides, the linear order of which encodes an organism's genetic blueprint. However, the genome does not exist as a linear entity within cells where this blueprint is actually utilized. Inside the nucleus, the genome is organized in three-dimensional (3D) space, and lineage-specific transcriptional programs that direct stem cell fate are implemented in this native 3D context. Here, we review principles of 3D genome organization in mammalian cells. We focus on the emerging relationship between genome organization and lineage-specific transcriptional regulation, which we argue are inextricably linked. 10.1016/j.stem.2014.05.017
    From Loops to Looks: Transcription Factors and Chromatin Organization Shaping Terminal B Cell Differentiation. Azagra Alba,Marina-Zárate Ester,Ramiro Almudena R,Javierre Biola M,Parra Maribel Trends in immunology B lymphopoiesis is tightly regulated at the level of gene transcription. In recent years, investigators have shed light on the transcription factor networks and the epigenetic machinery involved at all differentiation steps of mammalian B cell development. During terminal differentiation, B cells undergo dramatic changes in gene transcriptional programs to generate germinal center B cells, plasma cells and memory B cells. Recent evidence indicates that mature B cell formation involves an essential contribution from 3D chromatin conformations through its interplay with transcription factors and epigenetic machinery. Here, we provide an up-to-date overview of the coordination between transcription factors, epigenetic changes, and chromatin architecture during terminal B cell differentiation, focusing on recent discoveries and technical advances for studying 3D chromatin structures. 10.1016/j.it.2019.11.006
    Genome architecture: domain organization of interphase chromosomes. Bickmore Wendy A,van Steensel Bas Cell The architecture of interphase chromosomes is important for the regulation of gene expression and genome maintenance. Chromosomes are linearly segmented into hundreds of domains with different protein compositions. Furthermore, the spatial organization of chromosomes is nonrandom and is characterized by many local and long-range contacts among genes and other sequence elements. A variety of genome-wide mapping techniques have made it possible to chart these properties at high resolution. Combined with microscopy and computational modeling, the results begin to yield a more coherent picture that integrates linear and three-dimensional (3D) views of chromosome organization in relation to gene regulation and other nuclear functions. 10.1016/j.cell.2013.02.001
    Transcription factors and 3D genome conformation in cell-fate decisions. Stadhouders Ralph,Filion Guillaume J,Graf Thomas Nature How cells adopt different identities has long fascinated biologists. Signal transduction in response to environmental cues results in the activation of transcription factors that determine the gene-expression program characteristic of each cell type. Technological advances in the study of 3D chromatin folding are bringing the role of genome conformation in transcriptional regulation to the fore. Characterizing this role of genome architecture has profound implications, not only for differentiation and development but also for diseases including developmental malformations and cancer. Here we review recent studies indicating that the interplay between transcription and genome conformation is a driving force for cell-fate decisions. 10.1038/s41586-019-1182-7
    Regulation of Genome Architecture and Function by Polycomb Proteins. Entrevan Marianne,Schuettengruber Bernd,Cavalli Giacomo Trends in cell biology Polycomb group (PcG) proteins dynamically define cellular identities through the epigenetic repression of key developmental regulatory genes. PcG proteins are recruited to specific regulatory elements to modify the chromatin surrounding them. In addition, they regulate the organization of their target genes in the 3D space of the nucleus, and this regulatory function of the 3D genome architecture is involved in cell differentiation and the maintenance of cellular memory. In this review we discuss recent advances in our understanding of how PcG proteins are recruited to chromatin to induce local and global changes in chromosome conformation and regulate their target genes. 10.1016/j.tcb.2016.04.009
    Regulation of genome organization and gene expression by nuclear mechanotransduction. Uhler Caroline,Shivashankar G V Nature reviews. Molecular cell biology It is well established that cells sense chemical signals from their local microenvironment and transduce them to the nucleus to regulate gene expression programmes. Although a number of experiments have shown that mechanical cues can also modulate gene expression, the underlying mechanisms are far from clear. Nevertheless, we are now beginning to understand how mechanical cues are transduced to the nucleus and how they influence nuclear mechanics, genome organization and transcription. In particular, recent progress in super-resolution imaging, in genome-wide application of RNA sequencing, chromatin immunoprecipitation and chromosome conformation capture and in theoretical modelling of 3D genome organization enables the exploration of the relationship between cell mechanics, 3D chromatin configurations and transcription, thereby shedding new light on how mechanical forces regulate gene expression. 10.1038/nrm.2017.101
    Regulatory Landscaping: How Enhancer-Promoter Communication Is Sculpted in 3D. Robson Michael I,Ringel Alessa R,Mundlos Stefan Molecular cell During embryogenesis, precise gene transcription in space and time requires that distal enhancers and promoters communicate by physical proximity within gene regulatory landscapes. To achieve this, regulatory landscapes fold in nuclear space, creating complex 3D structures that influence enhancer-promoter communication and gene expression and that, when disrupted, can cause disease. Here, we provide an overview of how enhancers and promoters construct regulatory landscapes and how multiple scales of 3D chromatin structure sculpt their communication. We focus on emerging views of what enhancer-promoter contacts and chromatin domains physically represent and how two antagonistic fundamental forces-loop extrusion and homotypic attraction-likely form them. We also examine how these same forces spatially separate regulatory landscapes by functional state, thereby creating higher-order compartments that reconfigure during development to enable proper enhancer-promoter communication. 10.1016/j.molcel.2019.05.032
    Regulation of disease-associated gene expression in the 3D genome. Krijger Peter Hugo Lodewijk,de Laat Wouter Nature reviews. Molecular cell biology Genetic variation associated with disease often appears in non-coding parts of the genome. Understanding the mechanisms by which this phenomenon leads to disease is necessary to translate results from genetic association studies to the clinic. Assigning function to this type of variation is notoriously difficult because the human genome harbours a complex regulatory landscape with a dizzying array of transcriptional regulatory sequences, such as enhancers that have unpredictable, promiscuous and context-dependent behaviour. In this Review, we discuss how technological advances have provided increasingly detailed information on genome folding; for example, genome folding forms loops that bring enhancers and target genes into close proximity. We also now know that enhancers function within topologically associated domains, which are structural and functional units of chromosomes. Studying disease-associated mutations and chromosomal rearrangements in the context of the 3D genome will enable the identification of dysregulated target genes and aid the progression from descriptive genetic association results to discovering molecular mechanisms underlying disease. 10.1038/nrm.2016.138
    The hierarchy of the 3D genome. Gibcus Johan H,Dekker Job Molecular cell Mammalian genomes encode genetic information in their linear sequence, but appropriate expression of their genes requires chromosomes to fold into complex three-dimensional structures. Transcriptional control involves the establishment of physical connections among genes and regulatory elements, both along and between chromosomes. Recent technological innovations in probing the folding of chromosomes are providing new insights into the spatial organization of genomes and its role in gene regulation. It is emerging that folding of large complex chromosomes involves a hierarchy of structures, from chromatin loops that connect genes and enhancers to larger chromosomal domains and nuclear compartments. The larger these structures are along this hierarchy, the more stable they are within cells, while becoming more stochastic between cells. Here, we review the experimental and theoretical data on this hierarchy of structures and propose a key role for the recently discovered topologically associating domains. 10.1016/j.molcel.2013.02.011
    Organization and function of the 3D genome. Bonev Boyan,Cavalli Giacomo Nature reviews. Genetics Understanding how chromatin is organized within the nucleus and how this 3D architecture influences gene regulation, cell fate decisions and evolution are major questions in cell biology. Despite spectacular progress in this field, we still know remarkably little about the mechanisms underlying chromatin structure and how it can be established, reset and maintained. In this Review, we discuss the insights into chromatin architecture that have been gained through recent technological developments in quantitative biology, genomics and cell and molecular biology approaches and explain how these new concepts have been used to address important biological questions in development and disease. 10.1038/nrg.2016.112
    Analysis methods for studying the 3D architecture of the genome. Ay Ferhat,Noble William S Genome biology The rapidly increasing quantity of genome-wide chromosome conformation capture data presents great opportunities and challenges in the computational modeling and interpretation of the three-dimensional genome. In particular, with recent trends towards higher-resolution high-throughput chromosome conformation capture (Hi-C) data, the diversity and complexity of biological hypotheses that can be tested necessitates rigorous computational and statistical methods as well as scalable pipelines to interpret these datasets. Here we review computational tools to interpret Hi-C data, including pipelines for mapping, filtering, and normalization, and methods for confidence estimation, domain calling, visualization, and three-dimensional modeling. 10.1186/s13059-015-0745-7
    The 3D Genome as Moderator of Chromosomal Communication. Dekker Job,Mirny Leonid Cell Proper expression of genes requires communication with their regulatory elements that can be located elsewhere along the chromosome. The physics of chromatin fibers imposes a range of constraints on such communication. The molecular and biophysical mechanisms by which chromosomal communication is established, or prevented, have become a topic of intense study, and important roles for the spatial organization of chromosomes are being discovered. Here we present a view of the interphase 3D genome characterized by extensive physical compartmentalization and insulation on the one hand and facilitated long-range interactions on the other. We propose the existence of topological machines dedicated to set up and to exploit a 3D genome organization to both promote and censor communication along and between chromosomes. 10.1016/j.cell.2016.02.007
    Structural variation in the 3D genome. Spielmann Malte,Lupiáñez Darío G,Mundlos Stefan Nature reviews. Genetics Structural and quantitative chromosomal rearrangements, collectively referred to as structural variation (SV), contribute to a large extent to the genetic diversity of the human genome and thus are of high relevance for cancer genetics, rare diseases and evolutionary genetics. Recent studies have shown that SVs can not only affect gene dosage but also modulate basic mechanisms of gene regulation. SVs can alter the copy number of regulatory elements or modify the 3D genome by disrupting higher-order chromatin organization such as topologically associating domains. As a result of these position effects, SVs can influence the expression of genes distant from the SV breakpoints, thereby causing disease. The impact of SVs on the 3D genome and on gene expression regulation has to be considered when interpreting the pathogenic potential of these variant types. 10.1038/s41576-018-0007-0
    Control of DNA replication timing in the 3D genome. Marchal Claire,Sima Jiao,Gilbert David M Nature reviews. Molecular cell biology The 3D organization of mammalian chromatin was described more than 30 years ago by visualizing sites of DNA synthesis at different times during the S phase of the cell cycle. These early cytogenetic studies revealed structurally stable chromosome domains organized into subnuclear compartments. Active-gene-rich domains in the nuclear interior replicate early, whereas more condensed chromatin domains that are largely at the nuclear and nucleolar periphery replicate later. During the past decade, this spatiotemporal DNA replication programme has been mapped along the genome and found to correlate with epigenetic marks, transcriptional activity and features of 3D genome architecture such as chromosome compartments and topologically associated domains. But the causal relationship between these features and DNA replication timing and the regulatory mechanisms involved have remained an enigma. The recent identification of cis-acting elements regulating the replication time and 3D architecture of individual replication domains and of long non-coding RNAs that coordinate whole chromosome replication provide insights into such mechanisms. 10.1038/s41580-019-0162-y
    Genome-wide mapping and analysis of chromosome architecture. Schmitt Anthony D,Hu Ming,Ren Bing Nature reviews. Molecular cell biology Chromosomes of eukaryotes adopt highly dynamic and complex hierarchical structures in the nucleus. The three-dimensional (3D) organization of chromosomes profoundly affects DNA replication, transcription and the repair of DNA damage. Thus, a thorough understanding of nuclear architecture is fundamental to the study of nuclear processes in eukaryotic cells. Recent years have seen rapid proliferation of technologies to investigate genome organization and function. Here, we review experimental and computational methodologies for 3D genome analysis, with special focus on recent advances in high-throughput chromatin conformation capture (3C) techniques and data analysis. 10.1038/nrm.2016.104
    Architectural proteins: regulators of 3D genome organization in cell fate. Gómez-Díaz Elena,Corces Victor G Trends in cell biology The relation between alterations in chromatin structure and changes in gene expression during cell differentiation has served as a paradigm to understand the link between genome organization and function. Yet, the factors involved and the mechanisms by which the 3D organization of the nucleus is established remain poorly understood. The use of Chromosome Conformation-Capture (3C)-based approaches has resulted in a new appreciation of the role of architectural proteins in the establishment of 3D genome organization. Architectural proteins orchestrate higher-order chromatin organization through the establishment of interactions between regulatory elements across multiple spatial scales. The regulation of these proteins, their interaction with DNA, and their co-occurrence in the genome, may be responsible for the plasticity of 3D chromatin architecture that dictates cell and time-specific blueprints of gene expression. 10.1016/j.tcb.2014.08.003
    Organizational principles of 3D genome architecture. Rowley M Jordan,Corces Victor G Nature reviews. Genetics Studies of 3D chromatin organization have suggested that chromosomes are hierarchically organized into large compartments composed of smaller domains called topologically associating domains (TADs). Recent evidence suggests that compartments are smaller than previously thought and that the transcriptional or chromatin state is responsible for interactions leading to the formation of small compartmental domains in all organisms. In vertebrates, CTCF forms loop domains, probably via an extrusion process involving cohesin. CTCF loops cooperate with compartmental domains to establish the 3D organization of the genome. The continuous extrusion of the chromatin fibre by cohesin may also be responsible for the establishment of enhancer-promoter interactions and stochastic aspects of the transcription process. These observations suggest that the 3D organization of the genome is an emergent property of chromatin and its components, and thus may not be only a determinant but also a consequence of its function. 10.1038/s41576-018-0060-8
    Methods for mapping 3D chromosome architecture. Kempfer Rieke,Pombo Ana Nature reviews. Genetics Determining how chromosomes are positioned and folded within the nucleus is critical to understanding the role of chromatin topology in gene regulation. Several methods are available for studying chromosome architecture, each with different strengths and limitations. Established imaging approaches and proximity ligation-based chromosome conformation capture (3C) techniques (such as DNA-FISH and Hi-C, respectively) have revealed the existence of chromosome territories, functional nuclear landmarks (such as splicing speckles and the nuclear lamina) and topologically associating domains. Improvements to these methods and the recent development of ligation-free approaches, including GAM, SPRITE and ChIA-Drop, are now helping to uncover new aspects of 3D genome topology that confirm the nucleus to be a complex, highly organized organelle. 10.1038/s41576-019-0195-2
    The role of 3D genome organization in development and cell differentiation. Zheng Hui,Xie Wei Nature reviews. Molecular cell biology In eukaryotes, the genome does not exist as a linear molecule but instead is hierarchically packaged inside the nucleus. This complex genome organization includes multiscale structural units of chromosome territories, compartments, topologically associating domains, which are often demarcated by architectural proteins such as CTCF and cohesin, and chromatin loops. The 3D organization of chromatin modulates biological processes such as transcription, DNA replication, cell division and meiosis, which are crucial for cell differentiation and animal development. In this Review, we discuss recent progress in our understanding of the general principles of chromatin folding, its regulation and its functions in mammalian development. Specifically, we discuss the dynamics of 3D chromatin and genome organization during gametogenesis, embryonic development, lineage commitment and stem cell differentiation, and focus on the functions of chromatin architecture in transcription regulation. Finally, we discuss the role of 3D genome alterations in the aetiology of developmental disorders and human diseases. 10.1038/s41580-019-0132-4
    Mechanisms of Interplay between Transcription Factors and the 3D Genome. Kim Seungsoo,Shendure Jay Molecular cell Transcription factors (TFs) bind DNA in a sequence-specific manner and thereby serve as the protein anchors and determinants of 3D genome organization. Conversely, chromatin conformation shapes TF activity, for example, by looping TF-bound enhancers to distally located target genes. Despite considerable effort, our understanding of the mechanistic relation between TFs and 3D genome organization remains limited, in large part due to this interdependency. In this review, we summarize the evidence for the diverse mechanisms by which TFs and their activity shape the 3D genome and vice versa. We further highlight outstanding questions and potential approaches for untangling the complex relation between TF activity and the 3D genome. 10.1016/j.molcel.2019.08.010