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March 17, 2017

3D Single-Cell Genome Structures Compared, Contrasted

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    Intact genome from one particular mouse embryonic stem cell. Each of the cell’s 20 chromosomes is colored differently. [University of Cambridge and MRC Laboratory of Molecular Biology]

    The cell’s nucleus is like a densely packed but busy archive, one that resorts to the use of mobile shelving, which consists of wheeled shelving units that run along tracks—pushed together to save space, then separated to facilitate access, when needed. In the nucleus, where the mobile shelving units consist of chromosomal structures and genomic DNA domains, some order is maintained despite the constant shuttling of information, not to mention the occasional copying project, necessary for cell division. Characterizing this order is essential to understanding the cell’s normal function, as well as its dysfunction.

    To get a feel for the usual disposition of the genomic shelving units in individual cells, scientists at the University of Cambridge and the MRC Laboratory of Molecular Biology calculated 3D structures of entire mammalian genomes using data from a new chromosome conformation capture procedure. The new procedure, the scientists report, allowed them to first image and then process single cells.

    Essentially, the scientist used a combination of imaging and up to 100,000 measurements of where different parts of the DNA are close to each other to examine the genome in a mouse embryonic stem cell. Ultimately, the scientists managed to determine the first 3D structures of intact mammalian genomes from individual cells, showing how the DNA from all the chromosomes intricately folds to fit together inside the cell nuclei.

    Details of this work appeared March 13 in the journal Nature, in an article entitled, “3D Structures of Individual Mammalian Genomes Studied by Single-Cell Hi-C.” This article describes how the researchers were able to examine genome folding at a scale of less than 100 kb. This resolution allowed the researchers to validate chromosome structures.

    “The structures of individual topological-associated domains and loops vary substantially from cell to cell,” the article’s authors wrote. “By contrast, A and B compartments, lamina-associated domains and active enhancers and promoters are organized in a consistent way on a genome-wide basis in every cell, suggesting that they could drive chromosome and genome folding.”

    Most people are familiar with the well-known "X" shape of chromosomes, but in fact chromosomes only take on this shape when the cell divides. Using their new approach, the researchers have now been able to determine the structures of active chromosomes inside the cell, and how they interact with each other to form an intact genome.

    This is important because knowledge of the way DNA folds inside the cell allows scientists to study how specific genes, and the DNA regions that control them, interact with each other. The genome's structure controls when and how strongly genes—particular regions of the DNA—are switched “on” or “off.” This plays a critical role in the development of organisms and also, when it goes awry, in disease.

    The researchers found that the genome is arranged such that the most active genetic regions are on the interior and separated in space from the less active regions that associate with the nuclear lamina. The consistent segregation of these regions, in the same way in every cell, suggests that these processes could drive chromosome and genome folding and thus regulate important cellular events such as DNA replication and cell division.

    "Knowing where all the genes and control elements are at a given moment will help us understand the molecular mechanisms that control and maintain their expression,” commented Prof. Ernest Laue, whose group at Cambridge's Department of Biochemistry developed the new imaging approach. "In the future, we'll be able to study how this changes as stem cells differentiate and how decisions are made in individual developing stem cells."

    “Until now, we've only been able to look at groups, or 'populations', of these cells and so have been unable to see individual differences, at least from the outside. Currently, these mechanisms are poorly understood and understanding them may be key to realizing the potential of stem cells in medicine."

    "Visualizing a genome in 3D at such an unprecedented level of detail is an exciting step forward in research and one that has been many years in the making,” stated Tom Collins, Ph.D., from Wellcome's Genetics and Molecular Sciences team. “This detail will reveal some of the underlying principles that govern the organization of our genomes—for example how chromosomes interact or how structure can influence whether genes are switched on or off. If we can apply this method to cells with abnormal genomes, such as cancer cells, we may be able to better understand what exactly goes wrong to cause disease, and how we could develop solutions to correct this."

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