The Three-Dimensional Organization of Mammalian Genomes.

Animal development depends on not only the linear genome sequence that embeds millions of cis-regulatory elements, but also the three-dimensional (3D) chromatin architecture that orchestrates the interplay between cis-regulatory elements and their target genes. Compared to our knowledge of the cis-regulatory sequences, the understanding of the 3D genome organization in human and other eukaryotes is still limited. Recent advances in technologies to map the 3D genome architecture have greatly accelerated the pace of discovery. Here, we review emerging concepts of chromatin organization in mammalian cells, discuss the dynamics of chromatin conformation during development, and highlight important roles for chromatin organization in cancer and other human diseases.

[1]  Bing Ren,et al.  Whole-genome haplotype reconstruction using proximity-ligation and shotgun sequencing , 2013, Nature Biotechnology.

[2]  Sigal Shachar,et al.  3D Chromosome Regulatory Landscape of Human Pluripotent Cells. , 2016, Cell stem cell.

[3]  A. Tanay,et al.  Single cell Hi-C reveals cell-to-cell variability in chromosome structure , 2013, Nature.

[4]  Yaojun Zhang,et al.  3D Trajectories Adopted by Coding and Regulatory DNA Elements: First-Passage Times for Genomic Interactions , 2014, Cell.

[5]  L. Ettwiller,et al.  Functional and topological characteristics of mammalian regulatory domains , 2014, Genome research.

[6]  A. Murray,et al.  Interphase chromosomes undergo constrained diffusional motion in living cells , 1997, Current Biology.

[7]  R. Shiekhattar,et al.  Architectural and Functional Commonalities between Enhancers and Promoters , 2015, Cell.

[8]  N. Galjart,et al.  CTCF mediates long-range chromatin looping and local histone modification in the beta-globin locus. , 2007, Genes & development.

[9]  Enrique Blanco,et al.  3 D structure of individual mammalian genomes studied by single cell HiC , 2017 .

[10]  Philip D. Gregory,et al.  Reactivation of Developmentally Silenced Globin Genes by Forced Chromatin Looping , 2014, Cell.

[11]  David A. Orlando,et al.  Mediator and Cohesin Connect Gene Expression and Chromatin Architecture , 2010, Nature.

[12]  Ana Pombo,et al.  Replicon Clusters Are Stable Units of Chromosome Structure: Evidence That Nuclear Organization Contributes to the Efficient Activation and Propagation of S Phase in Human Cells , 1998, The Journal of cell biology.

[13]  Michael D. Wilson,et al.  Topoisomerase II beta interacts with cohesin and CTCF at topological domain borders , 2016, Genome Biology.

[14]  Bo Huang,et al.  Imaging Specific Genomic DNA in Living Cells. , 2016, Annual review of biophysics.

[15]  Melike Lakadamyali,et al.  Advanced microscopy methods for visualizing chromatin structure , 2015, FEBS letters.

[16]  A. Visel,et al.  Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions , 2015, Cell.

[17]  Erik Splinter,et al.  Looping and interaction between hypersensitive sites in the active beta-globin locus. , 2002, Molecular cell.

[18]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[19]  Neva C. Durand,et al.  Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes , 2015, Proceedings of the National Academy of Sciences.

[20]  Dirk Schübeler,et al.  Global Reorganization of Replication Domains During Embryonic Stem Cell Differentiation , 2008, PLoS biology.

[21]  G. Felsenfeld,et al.  Insulators: exploiting transcriptional and epigenetic mechanisms , 2006, Nature Reviews Genetics.

[22]  Helen E. Parkinson,et al.  The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog) , 2016, Nucleic Acids Res..

[23]  Thomas G. Gilgenast,et al.  Local Genome Topology Can Exhibit an Incompletely Rewired 3D-Folding State during Somatic Cell Reprogramming. , 2016, Cell stem cell.

[24]  S. Grewal,et al.  Chromosome domain architecture and dynamic organization of the fission yeast genome , 2015, FEBS letters.

[25]  Cameron S. Osborne,et al.  The pluripotent regulatory circuitry connecting promoters to their long-range interacting elements , 2015, Genome research.

[26]  R. Young,et al.  Transcriptional Regulation and Its Misregulation in Disease , 2013, Cell.

[27]  J. Hayes,et al.  Intra- and inter-nucleosome interactions of the core histone tail domains in higher-order chromatin structure , 2013, Chromosoma.

[28]  Thomas Cremer,et al.  Multicolor 3D fluorescence in situ hybridization for imaging interphase chromosomes. , 2008, Methods in molecular biology.

[29]  Neva C. Durand,et al.  A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping , 2014, Cell.

[30]  Noam Kaplan,et al.  High-throughput genome scaffolding from in-vivo DNA interaction frequency , 2013, Nature Biotechnology.

[31]  Shawn M. Gillespie,et al.  Insulator dysfunction and oncogene activation in IDH mutant gliomas , 2015, Nature.

[32]  A. Tanay,et al.  Cell-cycle dynamics of chromosomal organisation at single-cell resolution , 2016, Nature.

[33]  Louise S. Matheson,et al.  Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome , 2015, Nature Genetics.

[34]  B. Chadwick,et al.  The macrosatellite DXZ4 mediates CTCF-dependent long-range intrachromosomal interactions on the human inactive X chromosome. , 2012, Human molecular genetics.

[35]  Olivier Elemento,et al.  Multi-tiered Reorganization of the Genome during B Cell Affinity Maturation Anchored by a Germinal Center-Specific Locus Control Region. , 2016, Immunity.

[36]  Jill M Dowen,et al.  Control of Cell Identity Genes Occurs in Insulated Neighborhoods in Mammalian Chromosomes , 2014, Cell.

[37]  Francesco Ferrari,et al.  Genome-wide chromatin interactions of the Nanog locus in pluripotency, differentiation, and reprogramming. , 2013, Cell stem cell.

[38]  Anthony D. Schmitt,et al.  A Compendium of Chromatin Contact Maps Reveals Spatially Active Regions in the Human Genome. , 2016, Cell reports.

[39]  Andre J. Faure,et al.  3D structure of individual mammalian genomes studied by single cell Hi-C , 2017, Nature.

[40]  William Stafford Noble,et al.  Fine-scale chromatin interaction maps reveal the cis-regulatory landscape of human lincRNA genes , 2014, Nature Methods.

[41]  A. Pombo,et al.  Intermingling of Chromosome Territories in Interphase Suggests Role in Translocations and Transcription-Dependent Associations , 2006, PLoS biology.

[42]  Pedro P. Rocha,et al.  CTCF establishes discrete functional chromatin domains at the Hox clusters during differentiation , 2015, Science.

[43]  Jesse R. Dixon,et al.  Chromatin Domains: The Unit of Chromosome Organization. , 2016, Molecular cell.

[44]  Yanli Wang,et al.  Topologically associating domains are stable units of replication-timing regulation , 2014, Nature.

[45]  Jesse R. Dixon,et al.  Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells , 2013, Proceedings of the National Academy of Sciences.

[46]  Neidhard Paweletz,et al.  Walther Flemming: pioneer of mitosis research , 2001, Nature Reviews Molecular Cell Biology.

[47]  J. Dekker,et al.  Capturing Chromosome Conformation , 2002, Science.

[48]  Ilya M. Flyamer,et al.  Active chromatin and transcription play a key role in chromosome partitioning into topologically associating domains , 2016, Genome research.

[49]  Michael Q. Zhang,et al.  Integrative analysis of 111 reference human epigenomes , 2015, Nature.

[50]  L. Mirny,et al.  Formation of Chromosomal Domains in Interphase by Loop Extrusion , 2015, bioRxiv.

[51]  Anton Goloborodko,et al.  Compaction and segregation of sister chromatids via active loop extrusion , 2016, bioRxiv.

[52]  Michael Q. Zhang,et al.  CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function , 2015, Cell.

[53]  Job Dekker,et al.  Mapping the 3D genome: Aiming for consilience , 2016, Nature Reviews Molecular Cell Biology.

[54]  Shane J. Neph,et al.  A comparative encyclopedia of DNA elements in the mouse genome , 2014, Nature.

[55]  Robert-Jan Palstra,et al.  HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter. , 2012, Genome research.

[56]  I. Amit,et al.  Comprehensive mapping of long range interactions reveals folding principles of the human genome , 2011 .

[57]  T. Cremer,et al.  Towards many colors in FISH on 3D-preserved interphase nuclei , 2006, Cytogenetic and Genome Research.

[58]  Yan Li,et al.  A high-resolution map of three-dimensional chromatin interactome in human cells , 2013, Nature.

[59]  M. Spielmann,et al.  A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) , 2015, Human molecular genetics.

[60]  Brian J. Beliveau,et al.  Spatial organization of chromatin domains and compartments in single chromosomes , 2016, Science.

[61]  Jennifer E. Phillips-Cremins,et al.  Architectural Protein Subclasses Shape 3D Organization of Genomes during Lineage Commitment , 2013, Cell.

[62]  Wouter de Laat,et al.  CTCF mediates long-range chromatin looping and local histone modification in the beta-globin locus. , 2006, Genes & development.

[63]  Wei Li,et al.  Intrachromosomal looping is required for activation of endogenous pluripotency genes during reprogramming. , 2013, Cell stem cell.

[64]  A. Ashworth,et al.  Unbiased analysis of potential targets of breast cancer susceptibility loci by Capture Hi-C , 2014, Genome research.

[65]  M. Levine.  Transcriptional Enhancers in Animal Development and Evolution , 2010, Current Biology.

[66]  A. Tanay,et al.  Three-Dimensional Folding and Functional Organization Principles of the Drosophila Genome , 2012, Cell.

[67]  F. Collins,et al.  Potential etiologic and functional implications of genome-wide association loci for human diseases and traits , 2009, Proceedings of the National Academy of Sciences.

[68]  S. Mundlos,et al.  Formation of new chromatin domains determines pathogenicity of genomic duplications , 2016, Nature.

[69]  William Stafford Noble,et al.  Massively multiplex single-cell Hi-C , 2016, Nature Methods.

[70]  Yun Zhu,et al.  The pluripotent genome in three dimensions is shaped around pluripotency factors , 2013, Nature.

[71]  Paola Bovolenta,et al.  Evolutionary comparison reveals that diverging CTCF sites are signatures of ancestral topological associating domains borders , 2015, Proceedings of the National Academy of Sciences.

[72]  Niko Välimäki,et al.  CTCF/cohesin-binding sites are frequently mutated in cancer , 2015, Nature Genetics.

[73]  Peter H. L. Krijger,et al.  Cell-of-Origin-Specific 3D Genome Structure Acquired during Somatic Cell Reprogramming , 2016, Cell stem cell.

[74]  Philip A. Ewels,et al.  Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C , 2015, Nature Genetics.

[75]  Yaniv Lubling,et al.  Cell cycle dynamics of chromosomal organisation at single-cell resolution , 2016 .

[76]  Julien Dorier,et al.  Models that include supercoiling of topological domains reproduce several known features of interphase chromosomes , 2013, Nucleic acids research.

[77]  J. Dekker,et al.  Structural and functional diversity of Topologically Associating Domains , 2015, FEBS letters.

[78]  Matteo Pellegrini,et al.  Long-range chromatin contacts in embryonic stem cells reveal a role for pluripotency factors and polycomb proteins in genome organization. , 2013, Cell stem cell.

[79]  William Stafford Noble,et al.  Bipartite structure of the inactive mouse X chromosome , 2015, Genome Biology.

[80]  V. Corces,et al.  CTCF: Master Weaver of the Genome , 2009, Cell.

[81]  T. Cremer,et al.  Quantitative motion analysis of subchromosomal foci in living cells using four-dimensional microscopy. , 1999, Biophysical journal.

[82]  Jeannie T. Lee,et al.  Chromosomes. A comprehensive Xist interactome reveals cohesin repulsion and an RNA-directed chromosome conformation. , 2015, Science.

[83]  Ilya M. Flyamer,et al.  Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition , 2017, Nature.

[84]  Job Dekker,et al.  Two ways to fold the genome during the cell cycle: insights obtained with chromosome conformation capture , 2014, Epigenetics & Chromatin.

[85]  Robert S Illingworth,et al.  Spatial genome organization: contrasting views from chromosome conformation capture and fluorescence in situ hybridization , 2014, Genes & development.

[86]  Howard Y. Chang,et al.  HiChIP: efficient and sensitive analysis of protein-directed genome architecture , 2016, Nature Methods.

[87]  Job Dekker,et al.  Organization of the Mitotic Chromosome , 2013, Science.

[88]  Daning Lu,et al.  Chromosome conformation elucidates regulatory relationships in developing human brain , 2016, Nature.

[89]  Jesse R. Dixon,et al.  Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions , 2012, Nature.

[90]  Denis Paquette,et al.  Clustering of Tissue-Specific Sub-TADs Accompanies the Regulation of HoxA Genes in Developing Limbs , 2013, PLoS genetics.

[91]  Jonathan M. Cairns,et al.  Lineage-Specific Genome Architecture Links Enhancers and Non-coding Disease Variants to Target Gene Promoters , 2016, Cell.

[92]  W. Sung,et al.  Chromatin connectivity maps reveal dynamic promoter–enhancer long-range associations , 2013, Nature.

[93]  Andrew C. Adey,et al.  Chromosome-scale scaffolding of de novo genome assemblies based on chromatin interactions , 2013, Nature Biotechnology.

[94]  S. Cockroft,et al.  Transcription forms and remodels supercoiling domains unfolding large-scale chromatin structures , 2013, Nature Structural &Molecular Biology.

[95]  N. Cox,et al.  Obesity-associated variants within FTO form long-range functional connections with IRX3 , 2014, Nature.

[96]  P. Gregory,et al.  Controlling Long-Range Genomic Interactions at a Native Locus by Targeted Tethering of a Looping Factor , 2012, Cell.

[97]  S. Dalton,et al.  Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types. , 2010, Genome research.

[98]  J. Sedat,et al.  Spatial partitioning of the regulatory landscape of the X-inactivation centre , 2012, Nature.

[99]  Howard Y. Chang,et al.  Structural organization of the inactive X chromosome in the mouse , 2016, Nature.

[100]  Gos Micklem,et al.  Supporting Online Material Materials and Methods Figs. S1 to S50 Tables S1 to S18 References Identification of Functional Elements and Regulatory Circuits by Drosophila Modencode , 2022 .

[101]  Shane J. Neph,et al.  Systematic Localization of Common Disease-Associated Variation in Regulatory DNA , 2012, Science.

[102]  James T. Robinson,et al.  Juicebox Provides a Visualization System for Hi-C Contact Maps with Unlimited Zoom. , 2016, Cell systems.

[103]  Damian Roqueiro,et al.  Genome-wide analysis of local chromatin packing in Arabidopsis thaliana , 2015, Genome research.

[104]  J. Dekker,et al.  The long-range interaction landscape of gene promoters , 2012, Nature.

[105]  Peter H. L. Krijger,et al.  CTCF Binding Polarity Determines Chromatin Looping. , 2015, Molecular cell.

[106]  Nils Blüthgen,et al.  Reciprocal insulation analysis of Hi-C data shows that TADs represent a functionally but not structurally privileged scale in the hierarchical folding of chromosomes , 2017, Genome research.

[107]  Nir Friedman,et al.  Mapping Nucleosome Resolution Chromosome Folding in Yeast by Micro-C , 2015, Cell.

[108]  E. Liu,et al.  An Oestrogen Receptor α-bound Human Chromatin Interactome , 2009, Nature.

[109]  Raymond K. Auerbach,et al.  Extensive Promoter-Centered Chromatin Interactions Provide a Topological Basis for Transcription Regulation , 2012, Cell.

[110]  Daniel S. Day,et al.  Activation of proto-oncogenes by disruption of chromosome neighborhoods , 2015, Science.

[111]  P. Fraser,et al.  Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus , 2009, Nature.

[112]  M. Gobbi,et al.  Analysis of hundreds of cis-regulatory landscapes at high resolution in a single, high-throughput experiment , 2014, Nature Genetics.

[113]  Wange Lu,et al.  Klf4 organizes long-range chromosomal interactions with the oct4 locus in reprogramming and pluripotency. , 2013, Cell stem cell.

[114]  T. Misteli,et al.  An uncertainty principle in chromosome positioning. , 2003, Trends in cell biology.

[115]  C. Nusbaum,et al.  Chromosome Conformation Capture Carbon Copy (5C): a massively parallel solution for mapping interactions between genomic elements. , 2006, Genome research.

[116]  D. Ward,et al.  Immunological method for mapping genes on Drosophila polytene chromosomes. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[117]  Dariusz M Plewczynski,et al.  CTCF-Mediated Human 3D Genome Architecture Reveals Chromatin Topology for Transcription , 2015, Cell.

[118]  R. Eils,et al.  Three-Dimensional Maps of All Chromosomes in Human Male Fibroblast Nuclei and Prometaphase Rosettes , 2005, PLoS biology.

[119]  Daniel S. Day,et al.  Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control , 2016, Cell.

[120]  Miao Yu,et al.  Mapping of long-range chromatin interactions by proximity ligation-assisted ChIP-seq , 2016, Cell Research.

[121]  S. Lewis,et al.  Deletions of chromosomal regulatory boundaries are associated with congenital disease , 2014, Genome Biology.

[122]  Thomas Cremer,et al.  Replication-timing-correlated spatial chromatin arrangements in cancer and in primate interphase nuclei , 2008, Journal of Cell Science.

[123]  Tom Misteli,et al.  The Meaning of Gene Positioning , 2008, Cell.

[124]  J. Dekker,et al.  Condensin-Driven Remodeling of X-Chromosome Topology during Dosage Compensation , 2015, Nature.

[125]  F. Grosveld,et al.  High-resolution identification of balanced and complex chromosomal rearrangements by 4C technology , 2009, Nature Methods.

[126]  Peter Teague,et al.  Differences in the Localization and Morphology of Chromosomes in the Human Nucleus , 1999, The Journal of cell biology.

[127]  V. Corces,et al.  Enhancer function: new insights into the regulation of tissue-specific gene expression , 2011, Nature Reviews Genetics.

[128]  Neva C. Durand,et al.  Deletion of DXZ4 on the human inactive X chromosome alters higher-order genome architecture , 2016, Proceedings of the National Academy of Sciences.

[129]  Dmitry A Afonnikov,et al.  Comparison of the three-dimensional organization of sperm and fibroblast genomes using the Hi-C approach , 2015, Genome Biology.

[130]  Lusy Handoko,et al.  Dynamic Reorganization of Extremely Long-Range Promoter-Promoter Interactions between Two States of Pluripotency. , 2015, Cell stem cell.

[131]  Reza Kalhor,et al.  Genome architectures revealed by tethered chromosome conformation capture and population-based modeling , 2011, Nature Biotechnology.

[132]  Jing Liang,et al.  Chromatin architecture reorganization during stem cell differentiation , 2015, Nature.

[133]  Anthony D. Schmitt,et al.  Genome-wide mapping and analysis of chromosome architecture , 2016, Nature Reviews Molecular Cell Biology.

[134]  Robert Tjian,et al.  Looping Back to Leap Forward: Transcription Enters a New Era , 2014, Cell.

[135]  Guillaume J. Filion,et al.  Systematic Protein Location Mapping Reveals Five Principal Chromatin Types in Drosophila Cells , 2010, Cell.