In a new publication, University of Illinois School of Molecular & Cellular Biology researchers provide the first-ever comprehensive map of genomic regions near polycomb bodies in bone cancer cells. And, while mapping the genome around the polycomb repressive complex, the team led by professor Supriya Prasanth, and including Neha Chetlangia (PhD, ’26, Cell & Developmental Biology), discovered that the protein ORCA plays a key role in organizing the genome in these cancer cells and affects DNA replication timing.
“Polycomb-mediated 3D-genome organization controls replication timing” was published in Science Advances in June 2026 and done in collaboration with the Aladjem lab at the National Institutes of Health.
Each cell, cancers included, has its own unique “library” inside the nucleus with an organizational system tailored to its function. “Two libraries that have the same books will need to organize them in completely different ways based on any particular location’s needs and demographics,” Chetlangia said. If researchers could better understand the structure of cancerous nucleonic libraries, then they may uncover a more detailed picture of how they replicate.
In this study, Chetlangia and Prasanth, the head of the Department of Cell & Developmental Biology, focused on osteosarcoma cells, a type of bone cancer cell.
“Our study was unique in that it studied these cells which contain polycomb, or PcG, bodies: distinct nuclear structures associated with gene repression,” Chetlangia explained.
PcG bodies act like a library’s restricted access area; they’re where genes are locked away and turned off. That’s because they’re rich in chemical tags that act as “do not touch” labels and can be applied to DNA, effectively shutting off specific regions of the genome.
“These bodies are distinct foci in the nuclei of those cells. It’s well known that cancer cells have some kind of disturbed gene expression — that’s why they’re cancerous. So, we wanted to see if these PcG bodies are organizing the genome in such a way that is impacting gene expression or other cellular processes,” Chetlangia said.
To find out, the authors used Tyramide Signal Amplification sequencing (TSA-Seq), a specialized experimental technique developed in 2018 by Cell & Developmental Biology professor Andrew Belmont. “Sometimes you’re placed in the exact correct environment to address a question,” Chetlangia said.
Unlike methods that measure how different parts of the genome interact with one another, TSA-Seq uses a nuclear structure as a reference point and maps which regions of DNA are located nearby.
“It’s taking a central point in the nucleus and moving radially in different directions and seeing what DNA is present in each of those directions,” Chetlangia said. “You’re literally starting at the nucleus and walking along the DNA like a string and mapping from there. That allows us to see how the spatial genome is organized around these nuclear hubs.”
While mapping genome organization around polycomb bodies, the researchers found that ORCA, also known as the Origin Recognition Complex Associated protein, was frequently associated with these repressive nuclear environments.
“ORCA is a protein that primarily plays its role in cellular replication. But it also has another role with heterochromatic DNA, that is, DNA that is not very expressed. ORCA helps keeps sites, like PcG bodies, as more repressive environments,” Chetlangia said. Put simply, ORCA is the librarian who distributes the chemical tags that label certain volumes as “restricted,” and shushes any patron that becomes too rowdy.
After observing ORCA’s proximity to PcG bodies using TSA-Seq, they decided to deplete it. When the researchers did so, the organization of genomic regions around PcG bodies was altered.
“This disruption was also linked to changes in DNA replication timing, suggesting that the spatial arrangement of the genome around polycomb bodies helps influence when specific regions of DNA are copied,” Chetlangia said.
The full implications for cancer biology remain to be explored, according to the research team. However, this study identifies a new connection between a replication-associated protein, three-dimensional genome organization, and the timing of DNA replication.
“This study identifies how a replication protein is playing a role in genome organization,” Chetlangia said. “It also gives us an idea of what kind of consequences it would have in DNA replication: a critical process for the stability of the genome in both healthy and cancerous cells.”
From Dr. Supriya Prasanth:
In an independent study, graduate student Dazhen Liu and postdoctoral researcher Mohit Mishra, also from the Prasanth lab, discovered that the smallest subunit of the Origin Recognition Complex, Orc6, is a key regulator of chromatin remodeling during DNA replication and repair, helping preserve genome stability by coordinating replication with the DNA damage response. The findings were published in Nucleic Acids Research in June 2026.
Together, these studies reveal that proteins once thought to function primarily in DNA replication also play fundamental roles in organizing the genome and maintaining its stability. By uncovering these previously unrecognized functions, the research offers new insights into how cells preserve genome integrity and provides a foundation for understanding how disruptions in these processes may contribute to cancer and other diseases.
