The iconic X-shaped chromosome is well-known to biologists, but that shape represents only a brief moment in time when the cell is preparing to divide. Now researchers have developed a method to visualize a 3-dimensional model of the chromosome in its active form, revealing a more complete picture of the complex structure’s role.
In a study published in the journal Nature (1), a team of researchers led by Peter Fraser at Babraham Institute in Cambridge, UK described a single-cell Hi-C imaging technique that identifies thousands of individual chromatin contacts within a single nucleus, illustrating how chromosomal DNA is elaborately folded.
“I think it’s going to be hugely beneficial in terms of understanding how the genome is controlled,” explained Fraser. “The genome project gave us the sequence and there is a large proportion of the genome that is functional.… Understanding how [chromosomes] are folded up and contacting genes is going to be a massive task, but this is going to tell us a lot about how the genome functions and how it is regulated.”
Fraser said that the single-cell Hi-C approach—which also combines genome-wide computational analysis and structural modeling of single-copy X chromosomes—has enabled his lab to accurately map specific genes within the intricate folds of DNA, providing a better explanation of the connection between chromosome structure and variable gene expression in individual cells.
“Our computational analysis showed that active genes tend to be toward the surface of the chromosome territories, though not the same active gene domains in every cell,” said Fraser. “That seemed to fit with what we know about variability in gene expression and gene transcription.”
Fraser suggested that as the imaging resolution and coverage of his lab’s technique improves, the approach may even be used to reconstruct the entire genome in 3D and study the inner working of disease, such as chromosomal translocations involved in cancer.
“Nobody knows how translocation happens,” said Fraser. “It is thought that regions in proximity get double-strand breaks and then they get joined together aberrantly, so we’d be able to interrogate that kind of thing for every gene in the genome.”
For now though, Fraser’s next step will be conducting high-throughput sequencing to study hundreds of cells rather than just dozens at a time. “I think we have only just scratched the surface with this paper.”
1. Nagano et al. Single-cell Hi-C reveals cell-to-cell variability in chromosome structure. Nature (2013) 502:59-64.