How a Protein Complex Helps Organize and Compact DNA

If stretched out, the DNA in a human cell would be about 2 meters long, but the nucleus of the cell is only about 6 micrometers in diameter. This is similar to packing 24 miles of thread into a tennis ball, and it’s at the heart of one of the biggest questions about genetic material: how does so much information get packed into such small cells in the human body and stay accessible for unique transcription in different types of cells within the same body? 

For Brian Chan, PhD candidate in the biomedical engineering department, that means leaning on polymer physics theory to develop ways to describe that organizational process.

His research is focused on understanding how our DNA is organized within cells—particularly how cells manage to pack large amounts of DNA into a small space and how this organization affects gene expression. Coupled with his expertise in polymer physics theory, Chan relies on computer simulations to explore these processes with the guidance of his advisor, Michael Rubinstein, the Aleksandar S. Vesic Distinguished Professor in the Thomas Lord Department of Mechanical Engineering and Materials Science.

One key component of his research is examining a process called “loop extrusion,” where a protein complex named cohesin forms loops in the DNA. Cohesin plays a significant role in organizing and regulating DNA within cells. While the importance of cohesin in cell division was discovered in the late 1990s, the idea that it also plays a role when cells are not dividing became prevalent only recently.

“This work is the culmination of years of polymer physics training, developing new simulation methods and discussing with experimentalists to ensure biological relevance,” Chan shared. “I hope this work not only provides theoretical support to experimentalists who are trying to better understand and modify regulation of specific genes, but also forms the basis for further research into more complex aspects of genome organization like its dynamic properties.”

In the context of cell division, cohesin acts like a molecular “clamp” that helps hold sister chromatids, or the identical copies of a chromosome, together after DNA replication. This ensures proper chromosome separation during cell division, which is essential for the distribution of genetic material.

When cells are not dividing, this looping helps compact the DNA into specific regions, called topologically associated domains (TADs), which influence how genes are regulated. By making sure certain parts of the DNA are in contact with others, this process can either enhance or suppress gene expression. 

“I feel like our work is some of the first to help give a physical explanation for how this process occurs,” Chan shared.

The implications of his work are important for understanding diseases like cancer, where irregular DNA contact can lead to abnormal gene regulation. Chan hopes that the findings of this research can build a theoretical framework that could help experimentalists design strategies to modify DNA behavior, potentially leading to new treatments or interventions for those diseases.

“What we’re trying to do is apply a physics perspective,” Chan said. “I’m really trying to understand it beyond the molecular biology viewpoint.” 

Chan’s research also contributes to a deeper understanding of the physical processes behind DNA organization, offering a new perspective that integrates physics with biology. His approach could inspire further experimental studies that may lead to advancements in the field of genetic regulation.