Researchers have long realized the importance of DNA’s precisely arranged structure. But only recently have new technologies made it possible to explore this architecture deeply. With simulations, indirect measurements and better imaging, scientists hope to reveal more about how the nucleome’s intricate folds regulate healthy cells. Better views will also help scientists understand the role that disrupted nucleomes play in aging and diseases, such as progeria and cancer.
“It is conceivable that every nuclear process has an element of structure in it,” says molecular geneticist Bing Ren of the University of California, San Diego School of Medicine. “It’s surprising, in fact, that we studied DNA for so long and yet we still have relatively little understanding of its 3-D architecture.”Make that 4-D. Recent work shows that fully understanding the nucleome requires analysis of its rearrangements in space over time. A cell’s nucleome changes during the course of a single day as the cell responds to its environment.
Last year, the National Institutes of Health launched a five-year, 4-D Nucleome program, committing more than $120 million to identify better tools and techniques for mapping the complexities of the genome’s 4-D structure. Geneticists, molecular biologists, mathematicians, biophysicists and others are now on an ambitious quest to chart the ever-shifting nuclear terrain.
A nucleome is constantly changing. “Time means that stimuli are happening,” Aiden says. A cell may change its activity as temperature changes, or as its human takes off for a run or goes to sleep.
To explore the link between a nucleome’s architecture and its shifting actions over time, Rajapakse and his colleagues generated numerical representations of the relationships between shape and function in the human genome over a 56-hour period. The team paired structural analysis with a technique that measures which DNA instructions are being read and followed at any given time.
Nearly 2,000 genes shifted their shape, activity and position in relation to at least one other gene in the nucleome, the researchers reported in the Proceedings of the National Academy of Sciences in June. Two genes involved in regulating the body’s daily cycles (SN: 7/25/15, p. 24), CLOCK and PER2, perform a synchronized dance toward and away from each other in a dependable 24-hour pattern, increasing and decreasing their activity in opposition to one another. Even on Hi-C maps that reveal loops and connections of distant genome bits, the two genes are too far apart to show any physical contact.
The researchers say that existing structural analyses may miss important interactions between distant genes. Understanding the dynamic relationships between nuclear structure and genetic function, Rajapakse says, is the future of nucleome research. The scientists hope that mathematical analyses of the genome will identify important 4-D differences between various cell types and between healthy and diseased cells.
Scientists already know that disrupting the nucleome can cause disease. If the wrong sections of the genome end up next to each other, the controls intended for one gene may be applied to a different gene, with problematic results. In a study published in May in Cell, an international team of researchers produced limb malformations in mice by re-creating genetic alterations associated with hand and foot deformities in humans. Deleting or misplacing a chunk of genetic code can shift chromatin’s orientation, in this case resulting in fused, misshapen or extra digits, the team showed.
Altered nucleomes have also been linked to aging and aging disorders. Hutchinson-Gilford progeria syndrome, a fatal premature aging condition, results from mutations in the gene that encodes lamin A, a protein that normally supports the membrane surrounding the nucleus. In progeria, the nucleus becomes deformed and chromatin is damaged.
In June, a study in Science linked disrupted nucleomes to a different premature aging condition, Werner syndrome (SN: 5/30/15, p. 13). Werner syndrome results when cells fail to produce working WRN protein, which, like lamin A, stabilizes a genome’s 3-D structure. As a result, young adults suffer symptoms such as osteoporosis, cataracts and hair loss.
Even healthy cells show a tight link between genome structure and aging: Older nucleomes accumulate genetic damage and appear to compact less tightly. In 2006, scientists found that naturally aging cells showed similar structural changes to cells ravaged by progeria.In 2009, researchers identified eight genes that were moved away from their normal nuclear positions in breast cancer cells. The genes were so predictably misplaced that the scientists suggested looking at a gene’s position in the nucleus as a potential indicator of cancer.
Once they have the nucleome’s organizational rules in hand, some scientists, including Aiden, hope to engineer genomic loops in the lab. Because loops tightly control a gene’s activities, engineered loops could be used in gene therapies as a biological on/off switch for inserted genes, Aiden says.High-quality maps of the nucleome are poised to uncover rich biological truths, Aiden says. He views the task ahead as similar to early astronomy. For Galileo to discover that Jupiter had moons, or that the Milky Way was a galaxy packed full of stars, he simply had to point his telescope in the right direction.