Single cell Hi-C reveals cell-to-cell variability in chromosome structure

Large-scale chromosome structure and spatial nuclear arrangement have been linked to control of gene expression and DNA replication and repair. Genomic techniques based on chromosome conformation capture (3C) assess contacts for millions of loci simultaneously, but do so by averaging chromosome conformations from millions of nuclei. Here we introduce single-cell Hi-C, combined with genome-wide statistical analysis and structural modelling of single-copy X chromosomes, to show that individual chromosomes maintain domain organization at the megabase scale, but show variable cell-to-cell chromosome structures at larger scales. Despite this structural stochasticity, localization of active gene domains to boundaries of chromosome territories is a hallmark of chromosomal conformation. Single-cell Hi-C data bridge current gaps between genomics and microscopy studies of chromosomes, demonstrating how modular organization underlies dynamic chromosome structure, and how this structure is probabilistically linked with genome activity patterns.

[1]  T. Cremer,et al.  Chromosome territories, nuclear architecture and gene regulation in mammalian cells , 2001, Nature Reviews Genetics.

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

[3]  Wendy A Bickmore,et al.  Chromatin Motion Is Constrained by Association with Nuclear Compartments in Human Cells , 2002, Current Biology.

[4]  Cameron S. Osborne,et al.  Active genes dynamically colocalize to shared sites of ongoing transcription , 2004, Nature Genetics.

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

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

[7]  K. Sandhu,et al.  Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions , 2006, Nature Genetics.

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

[9]  Anne E Carpenter,et al.  Long-Range Directional Movement of an Interphase Chromosome Site , 2006, Current Biology.

[10]  P. Fraser,et al.  Nuclear organization of the genome and the potential for gene regulation , 2007, Nature.

[11]  A. Gregory Matera,et al.  Actin-dependent intranuclear repositioning of an active gene locus in vivo , 2007, The Journal of cell biology.

[12]  T. Cremer,et al.  Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions , 2007, Nature Reviews Genetics.

[13]  E. Heard,et al.  The ins and outs of gene regulation and chromosome territory organisation. , 2007, Current opinion in cell biology.

[14]  Cameron S. Osborne,et al.  Myc Dynamically and Preferentially Relocates to a Transcription Factory Occupied by Igh , 2007, PLoS biology.

[15]  T. Misteli.  Beyond the Sequence: Cellular Organization of Genome Function , 2011 .

[16]  Tobias A. Knoch,et al.  The 3D Structure of the Immunoglobulin Heavy-Chain Locus: Implications for Long-Range Genomic Interactions , 2008, Cell.

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

[18]  W. Bickmore,et al.  Stable Morphology, but Dynamic Internal Reorganisation, of Interphase Human Chromosomes in Living Cells , 2010, PloS one.

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

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

[21]  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.

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

[23]  Marc A. Martí-Renom,et al.  Bridging the Resolution Gap in Structural Modeling of 3D Genome Organization , 2011, PLoS Comput. Biol..

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

[25]  Robert S. Illingworth,et al.  Cell type-specific DNA methylation at intragenic CpG islands in the immune system. , 2011, Genome research.

[26]  D. Bazett-Jones,et al.  A view of the chromatin landscape. , 2012, Micron.

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

[28]  Amos Tanay,et al.  Robust 4C-seq data analysis to screen for regulatory DNA interactions , 2012, Nature Methods.

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

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

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

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