For decades the cell nucleus has been a black box of biology—scientists have understood little about its structure or the way it operates. But thanks in part to new visualization technologies, biologists have recently begun probing the architecture of the nucleus in real time. And they are discovering that this architecture appears to change as we age or fall ill or as our needs shift. In fact, the structure of nuclear components—chromosomes, RNA, protein complexes and other small bodies—could be as biologically important as the components themselves.

It is not surprising that the nucleus is carefully organized. The human genome’s 3.2 billion DNA base pairs have to be compacted 400,000-fold to fit within the tiny space—yet genes must also interact with one another there and with the machinery that transcribes them into proteins. Nuclear structure has historically been difficult to study because scientists had to rely on electron microscopy or antibody stains, which show cellular components only at single points in time. In the 1990s, however, biologists started using green fluorescent protein to observe nuclear components in living cells in real time, much like a movie. “A picture is worth 1,000 words, and I always like to say a movie is worth one million words,” says David L. Spector, a cell biologist at Cold Spring Harbor Laboratory.

One of first things biologists noticed was that genes reside in different parts of the nucleus depending on their activity. Chromosomal regions containing silent genes localize to condensed DNA regions in the outer periphery, whereas active genes stay in the roomier nuclear center, perhaps because there they can more easily share the transcription resources. But “like most things in biology, people have found exceptions,” notes Tom Misteli, a cell biologist at the National Cancer Institute. Sometimes active genes are on the periphery, and vice versa.

Chromosomes position themselves carefully relative to one another, too. Mouse olfactory cells contain the genes for 1,300 types of smell receptors, but only one of the genes turns on in each cell. In a 2006 paper researchers used fluorescent tags to show that a receptor gene becomes expressed only if it comes into physical contact with a specific part of chromosome 14. The idea is that “these two chromosomes come together in three-dimensional space, they kiss, and that’s how you get your regulation” of genetic activity, Misteli says. Chromosome “kissing” also appears to play a role in determining which X chromosome gets turned off in female cells, because only one copy is usually active.

Changes to nuclear structure can affect cellular function in dramatic ways. In April biologists Thomas Cremer and Boris ­Joffe­ of the Ludwig-Maximilians University in Munich noticed that the architecture of retina rod nuclei is inverted in nocturnal mice—condensed DNA sits at the center, with less condensed regions in the periphery. They had no idea why but eventually “came to the incredible idea that it might be related to vision,” Joffe says. The researchers compared the retinal nuclei of 38 species and found that those of nocturnal and crepuscular species—animals active at dusk or dawn—featured the inverted structure, whereas diurnal species had the more traditional layout. The inverted architecture seems to minimize light scattering, which allows them to see better in the dark, Joffe says, but it is unclear why.

Aging and disease are also associated with changes to nuclear architecture. Generally, as cells age, stores of condensed DNA at the nuclear periphery start migrating inward. In a study in the Journal of Cell Biology in 2008, Misteli and his colleagues identified four cancer-related genes that change positions when breast cells become cancerous. Structure can also influence risk; when chromosomes get too close to one another, cancer-causing chromosomal translocations occur more often. And bizarrely, the X chromosome moves closer to the center after epileptic seizures.

No one knows whether these kinds of changes to nuclear structure trigger aging and disease or result from them, or both. In any case, it is clear “that if you mess around with the [nuclear] architecture, you can get disease,” Misteli says. It might one day be possible to diagnose diseases and age-related problems simply by looking at nuclear snapshots, he adds.

Perhaps the biggest remaining mystery is how the nucleus gets organized in the first place. Do molecular scaffolds tether nuclear constituents in a deterministic way, or does genome activity affect positioning in a probabilistic manner? Evidence supports both theories, and Spector posits that RNA may play an important role. This past March he and his colleagues identified an RNA that helps to structure nuclear compartments called paraspeckles. Undoubtedly, the mechanisms controlling nuclear organization will prove to be varied and complex. As Spector puts it: “Things in biology tend to not be in black and white.”

Note: This article was originally printed with the title, "Nuclear Architecture."