Salk Institute, UCSD scientists decode DNA’s 3D shape – The San … – The San Diego Union-Tribune

DNA is compressed in the nucleus in a disorderly way that allows flexibility in how genes are turned on and off, according to a study by scientists from the Salk Institute and University of California San Diego.

This discovery was made with a new imaging technology devised by Salk researchers led by Clodagh OShea and carried out by UCSD researchers led by Mark Ellisman.

Published in Science, the study is available at j.mp/salkdna. OShea is listed as senior author with Ellisman as collaborator. The first author was Horng Ou, a researcher in OSheas lab.

Understanding DNAs 3D structure is expected to yield a better understanding of how defects in that structure relate to senescence and diseases, according to a perspective piece published along with the study.

In the nucleus, DNA is bound to proteins called histones to make a complex called chromatin, which in turn forms chromosomes. The degree of compression is extreme. Stretched out to form a line, the DNA in a single cell would extend about two meters, or about 6 1/2 feet. It must all fit into a nucleus of about 10 millionths of a meter.

What that means is that not all your DNA is accessible, OShea said. So even though the same DNA sequence is in every cell in your body, its structure in any cell nucleus can be different, which determines whether those DNA sequences can be accessed and used.

The fundamental question then is, well what's the structure of DNA in the nucleus, she said.

Existing models envision DNA as being grouped in increasingly large fibers, one inside another. But determining whether these models are correct has been stymied by the lack of imaging technology that can visualize chromatin.

Electron microscopy, one of the common tools to visualize such minute structures, doesnt work well with chromatin, OShea said. Thats because the chemical elements in chromatin dont provide sufficient contrast.

The Salk team solved that problem by using a fluorescent dye to stain the chromatin. When the dye was illuminated, it caused a metal to coat the DNA and associated proteins so they can be more easily detected by electron microscopy. They call this method ChromEMT.

The dye was already known, but it was the Salk teams idea to use it for imaging chromatin. The actual imaging, called "multi-tilt electron tomography" was performed by colleagues at University of California San Diego.

They found that chromatin is packed in clusters of various densities. The denser clusters are not as accessible as the looser cluster, OShea said. This provides a mechanism for allowing selective access to genes.

Previous hierarchy-based models didnt fit the experimental evidence of gene activation and suppression, OShea said. These models suggested that access would be allowed or denied at predictable, periodic intervals. The trouble with that is that one error would cause the whole intricate structure to fail.

By allowing DNA to be compressed into many separate clusters, with no grand structure, gene regulation can be take place independently. Moreover, a defect in one cluster wouldnt affect other clusters.

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Salk Institute, UCSD scientists decode DNA's 3D shape - The San ... - The San Diego Union-Tribune