Scientists have developed a novel approach to determine the 3D structures of chromosomes in single cells, using hundreds of measurements of where different parts of the DNA get close to one another. The research, by scientists at the Department of Biochemistry at Cambridge, working with colleagues at the Babraham Institute and the Weizmann Institute in Israel, was published in the journal Nature.
It took several years to develop all the computational tools to make this happen, but the structures we can now reconstruct from this high-quality data are quite striking. More importantly, this new approach is allowing us to study the variation in chromosome structure on a cell-by-cell basis.
The commonly illustrated "X" shape chromosome structure is only present when the cell divides. The researchers have now also been able to model the structure of chromosomes when they are active. This is extremely important because the way that DNA folds up in chromosome structures is intimately linked to the way that DNA is used. It controls when and how strongly genes (particular regions of the DNA) are expressed. This plays a critical role in the development of organisms and also, when it goes awry, in disease.
The structural models show the complex way in which DNA folds up into working chromosomes and thus where all the genes lie in three dimensions. This new approach will allow scientists to study how specific genes, and the DNA regions that control them, interact with each other, to better understand how chromosomes work.
Regions of the chromosome are coloured blue where genes are active and yellow where it interacts with the membrane that surrounds the nucleus. The structure shows that the chromosome is arranged such that the most active genetic regions, which also interact with other chromosomes, are separated in space from the less active regions (associated with a protein called Lamin-B1).
Tim Stevens, who wrote the software to calculate and visualise the structures whilst working in Professor Ernest Laue's group, commented: “It took several years to develop all the computational tools to make this happen, but the structures we can now reconstruct from this high-quality data are quite striking. More importantly, this new approach is allowing us to study the variation in chromosome structure on a cell-by-cell basis.
"Knowing where all the genes and control elements are at a given moment will help us understand the molecular mechanisms that control and maintain the genome. In the future we will be looking at the individual decisions made by single developing stem cells that in a population, at least from the outside, appear to be uniform. Currently, these mechanisms are poorly understood and understanding them may be key to realising the potential of stem cells in medicine."
Courtesy: Cambridge University.