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

The spatial organization of the genome inside the cell nucleus is tissue-specific and has been linked to several nuclear processes including gene activation, gene silencing, genomic imprinting, gene co-regulation, genome maintenance, DNA replication, DNA repair, immunoglobulin gene rearrangement, chromosomal translocations and X chromosome inactivation.

In fact, just about any nuclear/genome function has a spatial component that has been implicated in its control.

​Surprisingly, we know little about chromosome conformation and spatial organization or how they are established, mainly due to the considerable cell-to-cell variability observed, even among genotypically and phenotypically identical cells.

For example, fluorescence in situ hybridisation (FISH) analyses show that cells of a particular tissue have a non-random organization of the genome, but still display considerable variability in genome and chromosome conformations probably due to the dynamic nature of chromosomal structures.

Chromosome conformation capture (3C) and derivative methods (4C, 5C and Hi-C) have enabled the detection of probabilistic chromosome organisation, but do so by assessing populations of millions of cells. Such data can be used to estimate average conformations, but these cannot be assumed to represent a single or recurrent chromosomal or genome structure in all cells.

To circumvent this problem we have developed single cell Hi-C, which can detect tens of thousands of chromatin contacts in a single cell, allowing us for the first time to build and analyze 3D structural models of mammalian chromosomes in silico.

​ Single cell Hi-C data bridge current gaps between genomics and microscopy studies of chromosomes and genomes and will help us to understand genome regulation, which is a major contributor in control of health and ageing.

For more information see: Single-cell Hi-C reveals cell-to-cell variability in chromosome structure (2013) T Nagano, Y Lubling, TJ Stevens, S Schoenfelder, E Yaffe, W Dean, ED Laue, A Tanay & P Fraser
Nature 502 (7469), 59-64.

The extent to which spatial organization is a cause or consequence of genome functions is a current topic of considerable debate, however emerging data indicate that nuclear location and organization are drivers of genome functions, which in cooperation with other features such as epigenetic marks, non-coding RNAs and trans-factor binding bring about genome control.

Thus, genome spatial organization can be considered on a par with other epigenetic features that together contribute to overall genome regulation, and only by studying them together can we hope to understand the whole of genome control.
5 model bundles of the mouse chromosome

5-model bundles of the mouse X chromosome from three different Th1 cells at 500 kb resolution. H3K4me3 in blue, interchromosomal contacts in red and lamin associated regions yellow. (models by Tim Stevens)