Segmental folding of chromosomes: A basis for structural and regulatory chromosomal neighborhoods?

We discuss here a series of testable hypotheses concerning the role of chromosome folding into topologically associating domains (TADs). Several lines of evidence suggest that segmental packaging of chromosomal neighborhoods may underlie features of chromatin that span large domains, such as heterochromatin blocks, association with the nuclear lamina and replication timing. By defining which DNA elements preferentially contact each other, the segmentation of chromosomes into TADs may also underlie many properties of long‐range transcriptional regulation. Several observations suggest that TADs can indeed provide a structural basis to regulatory landscapes, by controlling enhancer sharing and allocation. We also discuss how TADs may shape the evolution of chromosomes, by causing maintenance of synteny over large chromosomal segments. Finally we suggest a series of experiments to challenge these ideas and provide concrete examples illustrating how they could be practically applied.

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

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

[3]  William Stafford Noble,et al.  A Three-Dimensional Model of the Yeast Genome , 2010, Nature.

[4]  Lee E. Edsall,et al.  Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. , 2010, Cell stem cell.

[5]  D. Kleinjan,et al.  Cis-ruption mechanisms: disruption of cis-regulatory control as a cause of human genetic disease. , 2009, Briefings in functional genomics & proteomics.

[6]  Jennifer A. Mitchell,et al.  Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells , 2010, Nature Genetics.

[7]  K. Howe,et al.  Genomic regulatory blocks encompass multiple neighboring genes and maintain conserved synteny in vertebrates. , 2007, Genome research.

[8]  A. Aszódi,et al.  H3K27me3 forms BLOCs over silent genes and intergenic regions and specifies a histone banding pattern on a mouse autosomal chromosome. , 2009, Genome research.

[9]  M. Sung,et al.  Spatial congregation of STAT binding directs selective nuclear architecture during T-cell functional differentiation , 2013, Genome research.

[10]  B. van Steensel,et al.  Chromatin domains in higher eukaryotes: insights from genome-wide mapping studies , 2009, Chromosoma.

[11]  Imen Lassadi,et al.  High‐resolution profiling of γH2AX around DNA double strand breaks in the mammalian genome , 2010, The EMBO journal.

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

[13]  D. Duboule,et al.  A Switch Between Topological Domains Underlies HoxD Genes Collinearity in Mouse Limbs , 2013, Science.

[14]  Lee E. Edsall,et al.  A map of the cis-regulatory sequences in the mouse genome , 2012, Nature.

[15]  J. Dekker,et al.  The hierarchy of the 3D genome. , 2013, Molecular cell.

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

[17]  Lee E. Edsall,et al.  Human DNA methylomes at base resolution show widespread epigenomic differences , 2009, Nature.

[18]  Shyam Prabhakar,et al.  Mapping cis-regulatory domains in the human genome using multi-species conservation of synteny. , 2005, Human molecular genetics.

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

[20]  L. Schermelleh,et al.  Functional nuclear organization of transcription and DNA replication: a topographical marriage between chromatin domains and the interchromatin compartment. , 2010, Cold Spring Harbor symposia on quantitative biology.

[21]  Wouter de Laat,et al.  A Regulatory Archipelago Controls Hox Genes Transcription in Digits , 2011, Cell.

[22]  M. Groudine,et al.  Functional and Mechanistic Diversity of Distal Transcription Enhancers , 2011, Cell.

[23]  B. Steensel,et al.  Chromatin organization: form to function. , 2013 .

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

[25]  Laurence Ettwiller,et al.  Large-scale analysis of the regulatory architecture of the mouse genome with a transposon-associated sensor , 2011, Nature Genetics.

[26]  D. Pinkel,et al.  Regional copy number–independent deregulation of transcription in cancer , 2006, Nature Genetics.

[27]  Miki Ebisuya,et al.  Ripples from neighbouring transcription , 2008, Nature Cell Biology.

[28]  Edith Heard,et al.  High-resolution analysis of epigenetic changes associated with X inactivation. , 2009, Genome research.

[29]  D. Duboule,et al.  Global control regions and regulatory landscapes in vertebrate development and evolution. , 2008, Advances in genetics.

[30]  B. Steensel,et al.  Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture–on-chip (4C) , 2006, Nature Genetics.

[31]  Dimos Gaidatzis,et al.  Step-Wise Methylation of Histone H3K9 Positions Heterochromatin at the Nuclear Periphery , 2012, Cell.

[32]  L. Wessels,et al.  Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions , 2008, Nature.

[33]  A. Feinberg,et al.  Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells , 2009, Nature Genetics.

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

[35]  G. Wray.  The evolutionary significance of cis-regulatory mutations , 2007, Nature Reviews Genetics.

[36]  A. MacKenzie,et al.  Is there a functional link between gene interdigitation and multi-species conservation of synteny blocks? , 2004, BioEssays : news and reviews in molecular, cellular and developmental biology.

[37]  Bas van Steensel,et al.  Genome Architecture: Domain Organization of Interphase Chromosomes , 2013, Cell.

[38]  F. Grosveld,et al.  Beta-globin regulation and long-range interactions. , 2008, Advances in genetics.

[39]  W. V. van IJcken,et al.  The inactive X chromosome adopts a unique three-dimensional conformation that is dependent on Xist RNA. , 2011, Genes & development.

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

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

[42]  M. Hosoya,et al.  Elimination of a long-range cis-regulatory module causes complete loss of limb-specific Shh expression and truncation of the mouse limb , 2005, Development.

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

[44]  Amos Tanay,et al.  Chromosomal domains: epigenetic contexts and functional implications of genomic compartmentalization. , 2013, Current opinion in genetics & development.

[45]  Kelly M. McGarvey,et al.  PcG Proteins, DNA Methylation, and Gene Repression by Chromatin Looping , 2008, PLoS biology.

[46]  S. Carroll.  Evo-Devo and an Expanding Evolutionary Synthesis: A Genetic Theory of Morphological Evolution , 2008, Cell.

[47]  M. Ohtsuka,et al.  A transposon-based chromosomal engineering method to survey a large cis-regulatory landscape in mice , 2009, Nature Genetics.

[48]  Hideki Tanizawa,et al.  Mapping of long-range associations throughout the fission yeast genome reveals global genome organization linked to transcriptional regulation , 2010, Nucleic acids research.

[49]  K. Sumiyama,et al.  A cluster of three long-range enhancers directs regional Shh expression in the epithelial linings , 2009, Development.

[50]  Tyrone Ryba,et al.  Chromatin-interaction compartment switch at developmentally regulated chromosomal domains reveals an unusual principle of chromatin folding , 2012, Proceedings of the National Academy of Sciences.

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

[52]  W. D. Laat,et al.  A Decade of 3c Technologies: Insights into Nuclear Organization References , 2022 .

[53]  Bo Wen,et al.  Large chromatin domains in pluripotent and differentiated cells. , 2012, Acta biochimica et biophysica Sinica.

[54]  Sandra Ruf,et al.  An integrated holo-enhancer unit defines tissue and gene specificity of the Fgf8 regulatory landscape. , 2013, Developmental cell.

[55]  Takeharu Nagai,et al.  Local nucleosome dynamics facilitate chromatin accessibility in living mammalian cells. , 2012, Cell reports.

[56]  D. Duboule,et al.  Inversion-induced disruption of the Hoxd cluster leads to the partition of regulatory landscapes , 2005, Nature Genetics.

[57]  P. Flicek,et al.  Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation. , 2010, Molecular cell.

[58]  B. van Steensel,et al.  Chromatin: constructing the big picture , 2011, The EMBO journal.

[59]  A. Tanay,et al.  Probabilistic modeling of Hi-C contact maps eliminates systematic biases to characterize global chromosomal architecture , 2011, Nature Genetics.

[60]  François Radvanyi,et al.  A Novel Epigenetic Phenotype Associated With the Most Aggressive Pathway of Bladder Tumor Progression , 2010, Journal of the National Cancer Institute.

[61]  K. Sneppen,et al.  Theoretical Analysis of Epigenetic Cell Memory by Nucleosome Modification , 2007, Cell.

[62]  Brian J. Stevenson,et al.  Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. , 2012, Genome research.

[63]  L. Mirny,et al.  Higher-order chromatin structure: bridging physics and biology. , 2012, Current opinion in genetics & development.

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

[65]  Robert A. H. White.  Packaging the fly genome: domains and dynamics. , 2012, Briefings in functional genomics.

[66]  D. Duboule,et al.  Impact of copy number variations (CNVs) on long-range gene regulation at the HoxD locus , 2012, Proceedings of the National Academy of Sciences.

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

[68]  Bernadett Papp,et al.  Genome-wide dynamics of replication timing revealed by in vitro models of mouse embryogenesis. , 2010, Genome research.

[69]  Howard Y. Chang,et al.  A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression , 2011, Nature.

[70]  Wouter de Laat,et al.  Identical cells with different 3D genomes; cause and consequences? , 2013, Current opinion in genetics & development.

[71]  Zhaohui S. Qin,et al.  Gene density, transcription, and insulators contribute to the partition of the Drosophila genome into physical domains. , 2012, Molecular cell.