An integrated view of the structure and function of the human 4D nucleome
Managing Big Data in the Cell Nucleus
Did you know that each of your cells contains over 6 billion base pairs of DNA? Stretched out, that DNA would be about three feet long. Yet it all has to fit inside the cell nucleus—a space just 0.000033 feet across. ¡Ay caramba! How does all that genetic information squeeze into such a tiny place?
What’s more, only part of that DNA sits in “cold storage.” Much of it must remain accessible so a cell knows whether it is a liver cell or a brain cell. And before a cell divides, all of it must be copied, turning 3 billion base pairs into 12 billion. The nucleus must look like Manhattan at rush hour.
And in many ways, it does. Manhattan is dense, noisy, and chaotic—traffic jams, crowds, constant motion—but it functions because underlying systems impose order on that chaos. The nucleus works the same way: molecules move randomly, colliding and diffusing, yet higher-level organization ensures that essential processes happen at the right place and time. Understanding that organization was the goal of a major National Institutes of Health program called the 4D Nucleome (4DN)—“nucleome” meaning a complete description of the cell nucleus in space and time analogous to genome, transcriptome, metabolome and proteome.
This ten-year international effort brought together more than 150 laboratories to study not only DNA, which stores genetic information, but also RNA—the working copies of that information—and the molecular machines that process RNA so cells can build and maintain their specialized structures.
The Gilbert lab at San Diego BioMed focuses on a particularly tricky question: how can DNA be duplicated without disrupting this intricate nuclear organization? Imagine duplicating Manhattan from the inside, while everything is still running.
It was therefore a great honor for the Gilbert lab to participate in the 4DN project for its entire decade. The consortium’s findings are summarized in an article published this week in Nature, featured on the journal’s cover.
The Gilbert lab’s contribution highlights a key insight: it’s not just DNA that gets copied. The entire chromosome structure—its proteins, organization, and supporting infrastructure—must be taken apart and rebuilt. This rebuilding provides an opportunity for change—and Mother Nature does not squander opportunities.
Over more than 30 years, the Gilbert lab has shown that chromosomes replicate in segments, called replication domains, and that the temporal order in which these domains are copied helps determine how chromosomes are organized and used. Different cell types copy these domains in different orders, and diseased cells always have specific domains that replicate at the wrong time.
Working with 4DN collaborators, the lab demonstrated that when and where a chromosome segment is copied affects the structure that forms afterward. Some regions become active and accessible, while others are tucked away into cold storage—still important, but not needed in that cell. The work also showed that replication domains are equivalent to the structural domains identified by other members of the 4DN, and revealed some of the molecular mechanisms that link structure to function.
This work helps explain how structure and function are linked inside the nucleus. Since disruptions in chromosome organization are found in virtually all diseases, understanding these mechanisms opens the door to correcting them. It may even allow scientists to guide cell fate—engineering cells for therapies when certain tissues are missing or overproduced. Stay tuned as the Gilbert lab continues exploring how changing the time and place of DNA replication might one day help engineer cells for regenerative medicine.