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

By Takashi Nagano, Yaniv Lubling, T. Stevens, Stefan Schoenfelder, Eitan Yaffe, W. Dean, E. Laue, Amos Tanay, Peter Fraser. Nature, 2013

1,512 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Plant Science

View Paper: https://www.semanticscholar.org/paper/813b35fe40985c036ee2adf13a5f769148f5e577

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Citations in the corpus

Mapping the Mouse Cell Atlas by Microwell-Seq. (2018, positive): “…analysis (Buenrostro et al., 2015; Cusanovich et al., 2015; Guo et al., 2017; Jin et al., 2015; Lorthongpanich et al., 2013; Mooijman et al., 2016; Nagano et al., 2013; Smallwood et al., 2014), and in situ analysis (Chen et al., 2015; Ke et al., 2013; Lee et al., Cell 172, 1091–1107, February 22,…”
Defining cell types and states with single-cell genomics (2015, methodology): “Peter Fraser and colleagues adapted Hi-C, a technique for measuring chromatin conformation (Lieberman-Aiden et al. 2009) to work in single cells (Nagano et al. 2013).”
Roles, Functions, and Mechanisms of Long Non-coding RNAs in Cancer (2016, background): “More recent technical developments have focused on higher-throughput analyses and these include circular chromosome conformation capture (4C) [66,67], chromosome conformation capture carbon copy (5C) [68], combined 3C-ChIP-cloning (6C) [69], chromatin interaction analysis with paired-end tag sequenc”
Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition (2017, methodology): “…our method was remarkably efficient at capturing chromosomal interactions: snHi-C revealed up to 1.9 × 10 6 contacts per cell after filtering, yielding 1–2 orders of magnitude more contacts than published single-cell Hi-C data 2 and exceeding contact frequencies in single-cell Hi-C preprints 9,10 .”
Single-Cell and Single-Molecule Analysis of Gene Expression Regulation (2016, background): “These technologies are applied mainly to cell populations and require cross-linking of macromolecular components; thus, they cannot be used to determine the physical distances between interacting regions (8, 107).”
HiCRep: assessing the reproducibility of Hi-C data using a stratum-adjusted correlation coefficient (2017, positive): “Although the interactions within the structures can be highly variable between different cell types, the domain structures, such as topologically associating domains (TADs), are stable across cell types (Dixon et al. 2012; Rapkin et al. 2012; Nagano et al. 2013).”
Genome-wide mapping and analysis of chromosome architecture (2016, methodology): “A key limitation of the method is that only a small number of unique chromatin contacts, up to 30,000 in the published work 38 , were detected.”
Revealing the vectors of cellular identity with single-cell genomics (2016, methodology): “…on RNA and protein, recent progress in epigenome analysis 192 has included assays for single-cell ChIP-seq (Drop-ChIP 26 ), single-cell ATAC-seq 27,28 , single-cell Hi-C 29 (a genome-wide derivative of the chromosome conformation capture (3C) technique), and single-cell DNA methylation 22–25 .”