Scientists have determined 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.
Researchers from University of Cambridge in the UK 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.
Stem cells are ‘master cells’, which can develop – or ‘differentiate’ – into almost any type of cell within the body.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, researchers said.
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 structure shows 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.
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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,” said Professor Ernest Laue, whose group at Cambridge’s Department of Biochemistry developed the approach.
“In the future, we will be able to study how this changes as stem cells differentiate and how decisions are made in individual developing stem cells,” said Laue. “Until now, we have 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 realising the potential of stem cells in medicine,” Laue said. “Visualising 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,” said Tom Collins from Wellcome-MRC Stem Cell Institute. The research was published in the journal Nature.