Genomic switches hidden in ‘Loop-ome’

By developing 3D maps of folded genomes scientists have discovered that a structural basis for gene regulation can produce different cell types.

A team of researchers at Harvard University have assembled the first high-resolution, 3D maps of entire folded genomes and found a kind of "genomic origami" that allows the same genome to produce different types of cells.

Using a technology called "in situ Hi-C" the team collected billions of snippets of DNA in order to analyse them for signs of loops. The study, published in Cell, was part of a project aiming to identify the loops in human genome and other genome folding patterns thought to be an essential part of genetic regulation.

"Our maps of looping have revealed thousands of hidden switches that scientists didn't know about before" said Miriam Huntley, a PhD student at the Harvard School of Engineering and Applied Sciences.

After several years of development the team got the resolution of the system to a biologically usable level, allowing visualisation of folding at individual gene level. The researchers used GPU processors that are typically used for producing computer graphics to find the loops. "Most of the tools that we used for this paper we had to create from scratch because the scale at which these experiments are performed is so unusual" Huntley said.

The scientists found series of rules that can be applied to loop formation within the genome: the loops are almost all span fewer than 2 million genetic letters; they rarely overlap; and they are almost always associated with a single protein, called CTCF. Also the CTCF elements that form a loop must be pointing at each other.

The team has discovered that the largest loops in the genome are only present in women. The PhD student Huntley pointed out: “the copy of the X chromosome that is off in females contains gigantic loops that are up to 30 times the size of anything we see in males.”

Another finding suggests that specific folds are found in humans and mice which may imply a preservation of genomes over nearly one hundred million years of evolution. The discovery suggests mammals share not only similar 1D genome sequences, but also similar 3D genome folding patterns.

Paper:

http://www.cell.com/cell/pdf/S0092-8674%2814%2901497-4.pdf

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