Molecular Medicine Israel

Imaging Chromatin to Deduce Function From Form

Researchers describe their tools for probing how the physical shape of the genome affects genes’ function

In the mid-1800s, Lionel Smith Beale, an English physician and microscopist at King’s College in London, peered through his microscope at a smear of saliva and mucus coughed up by a man with cancer of the larynx. Beale carefully drew what he saw: cells unconnected with each other and radically diverse in size and shape. He noted that the cells’ nuclei varied in number, size, and appearance. His observations, published in 1860, provide one of the first descriptions of how cancer can ripple and distort the typical appearance of the cell’s nucleus, a sign of the genetic havoc the disease wreaks.

More than 150 years later, scientists are still trying to understand how the physical shape of the genome changes in response to disorder and disease. To fit six and a half feet of DNA inside a single nucleus, the double helix wraps around coin-shaped histone proteins and packs tightly with the aid of other scaffold proteins, forming a macromolecule called chromatin. Scientists can describe some of the organizing principles of chromatin but are still seeking a more precise and dynamic understanding of chromatin’s three-dimensional shape.

Chromatin’s DNA coils expose some genes to the cell’s transcriptional machinery and hide others. That means gene regulation is to some extent ascribed to chromatin’s structure, says Clodagh O’Shea, a biochemist at the Salk Institute in La Jolla, California. “If we could see the structure of an individual gene, then we could understand it.”…

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