The_Scientist_-_December_2018

58 THE SCIENTIST | the-scientist.com

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I

n 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 descrip-

tions 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 under-

stand 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 his-

tone proteins and packs tightly with the aid of other scaffold pro-

teins, 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 chro-

matin’s three-dimensional shape.

Chromatin’s DNA coils expose some genes to the cell’s transcrip-

tional 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.”

The Scientist explored several chromatin imaging methods that

allow researchers to deduce function from form.

FINE DUSTING

RESEARCHER: Clodagh O’Shea, biochemist, Salk Institute for

Biological Studies, La Jolla, California

PROJECT: Tour chromatin in 3-D

CHALLENGE: The advent of super-resolution light microscopy

allows scientists to image structures as small as 10 nanometers,

making it possible to capture molecular details at the level of the

DNA strand itself—termed DNA’s “first-order” structure. At chro-

Uncloaking Chromatin’s Hidden Structures

Researchers are using new imaging strategies and technologies to see how

chromatin’s shape regulates genes and cell function.

BY MARISSA FESSENDEN