3D structures of individual mammalian genomes studied by single-cell Hi-C

Abstract

The folding of genomic DNA from the beads-on-a-string like structure of nucleosomes into higher order assemblies is critically linked to nuclear processes. We have calculated the first 3D structures of entire mammalian genomes using data from a new chromosome conformation capture procedure that allows us to first image and then process single cells. This has allowed us to study genome folding down to a scale of <100 kb and to validate the structures. We show that the structures of individual topological-associated domains and loops vary very substantially from cell-to-cell. By contrast, A/B compartments, lamin-associated domains and active enhancers/promoters are organized in a consistent way on a genome-wide basis in every cell, suggesting that they could drive chromosome and genome folding. Through studying pluripotency factor- and NuRD-regulated genes, we illustrate how single cell genome structure determination provides a novel approach for investigating biological processes.

Ice-sheet history revealed by fossils

“…As such, they could arise from weak preferences summed across many cells, with real contacts in individual cells frequently crossing TAD boundaries. Single-cell Hi-C (which does measure contacts in individual cells) has not yet given a definitive answer: the current study provides evidence that TADs do indeed exist in individual cells, whereas other recent analyses 12,13 have reached the opposite conclusion.…”

“…Nagano et al are only the second group to achieve this, and do so for cells exiting mitosis 13 . A major technical hurdle has prevented the wider adoption of this potentially powerful computational modelling -cells normally contain maternal and paternal copies of each chromosome, and these have similar DNA sequences but are folded differently.…”

Nuclear Repositioning of the Non-Translocated <b><i>HLXB9</i></b> Allele in the Leukaemia Cell Line GDM-1 Harbouring a t(6;7)(q23;q36)

“…Chromosome conformation capture-based studies highlighted the presence of topologically associated domains (TADs) in the cell nucleus, namely genomic DNA sequences identified by their large degree of reciprocal physical interactions and endowed with different properties. Transcriptionally active TADs or inactive TADs are located in the more internal or in the more peripheral nuclear compartment, respectively [Stevens et al, 2017], as previously defined by molecular cytogenetic methods. Moreover, TADs located at the periphery of the cell nucleus are endowed with relevant properties that favour association to the nuclear lamina (lamina-associated domains) [Kind et al, 2015].…”

MSTD: an efficient method for detecting multi-scale topological domains from symmetric and asymmetric 3D genomic maps

“…With the development of new technologies, more diverse chromatin data will be generated for solving unknown biological problems. For examples, single cell Hi-C maps provide an opportunity to study the conservation and heterogeneity from cell to cell, revealing more granular cellular functions and biological processes in cell cycle 37,38 . MSTD is a very flexible and powerful framework, which is expected to be applied to such new data in near future.…”