Every human cell must perform a remarkable feat of organization: fitting two meters of DNA into a nucleus only 10 microns in size. For Matheus Mello, a graduate student working with José Onuchic in Rice’s Center for Theoretical Biological Physics (CTBP), this puzzle is at the heart of his research. His work focuses on understanding the patterns that arise when chromatin, a complex of DNA and proteins, is compacted inside the nucleus.
“We have many different cells: cells that differentiate into neurons, into skin cells, and so on,” he said. “To do that, different genes need to be turned on and off. So, in each cell, we have parts of the genes that are active and parts that are inactive. And this plays a big role in how the chromatin is organized within the cell.”
These patterns of active and inactive portions of the genome vary between cell types and strongly influence how chromatin is organized. “The main thing we see in the large-scale organization of chromosomes is the phase separation between these regions of the chromatin that are actively being transcribed and the regions that are turned off,” Matheus explained.
While CTBP researchers have developed theoretical models to describe this behavior, most of the work has focused on segregation within a single chromosome. Matheus is expanding that view to the entire nucleus. “In a human cell, we have 46 chromosomes, and they interact with one another and with their environment,” he said. “My work focuses on using these physical models to study the structure and dynamics of all these 46 chromosomes’ interactions.”
To do this, he reduces complexity without losing essential information. “We can imagine the chromosome as a big polymer made up of beads where each bead is roughly 50,000 base pairs long. Each chromosome ranges from 1,000-5,000 beads, and the total size for all 46 chromosomes is roughly 100,000 beads,” said Matheus. On top of this simplified framework, he adds features that capture how chromosomes actually behave, such as phase separation, loops and the molecular machines that drive compaction.
So far, his simulations show that the distinct “territories” that chromosomes form are surprisingly stable. “Our calculations show that the movement of the territories is very, very slow, meaning that throughout one cell life cycle, the territories do not reorganize in the nucleus,” Matheus explained. “But the configuration inside that territory is dynamic; the chromatin that forms one territory is able to reorganize during the cell life cycle.” These calculations suggest that each chromosome has a strong “memory” of its initial position after it compacts during cell division.
Matheus’s path to Rice began with an internship in 2019 while he was an undergraduate in Brazil. “After that, I decided I wanted to come back to Rice for my Ph.D.,” he recalled. Initially planning to work on protein folding, he was drawn instead to chromosome modeling. “I was surprised that I ended up working with chromosomes, but it was really interesting to me.”
The CTBP, with its bi-weekly chromosome-focused meetings that bring together theorists and experimentalists, has been the perfect place to explore these questions. “We are always hearing the developments on the experimental side, and many collaborations have begun because of these presentations,” he said.
Looking ahead, Matheus is turning his attention to the broader environment of the nucleus. “The chromosomes are not alone in the nucleus,” he said. “We know that for humans and other mammals, chromosome interactions with the nuclear envelope and other organelles inside the nucleus are really important; they affect the structure and have functional roles as well.” With the CTBP’s collaborative network and mentorship, he is excited to keep tackling the questions that drew him to Rice in the first place.