Understanding DNA's Complex 3D Architecture in the Cell

The human genome and its DNA are often presented in a single dimension in biology textbooks and educational materials. While introducing DNA as a linear sequence that produces genes can help students understand the basics, this approach overlooks the importance of the genome’s three-dimensional structure.

About six feet of DNA are packed into the cell nucleus by wrapping around protein spools called histones. In this compact state, known as chromatin, the DNA forms loops and clumps. These structures may seem disorganized, but they help protect certain regions of the genome and bring others into close contact.

Problems with chromatin structure are linked to several diseases, including cancer and developmental disorders. In breast cancer cells, approximately 12 % of genomic regions show abnormalities in chromatin structure. T-cell acute lymphoblastic leukemia involves a different type of structural disruption.

On June 27^th, 2025, researchers from Sanford Burnham Prebys and collaborators in Hong Kong published a study in Genome Biology. They introduced a new method for studying chromatin’s three-dimensional structure and its biological effects.

The researchers predicted that the 3D structure of genomic regions affects gene regulation.

We know that many regions of the genome tend to form what are known as topologically associating domains or TADs. Parts of the genome within these domains can interact more frequently with each other, while they tend to be isolated from the region outside this domain.

Kelly Yichen Li, Ph.D., Study Lead Author and Postdoctoral Associate, Sanford Burnham Prebys

Using spatial mapping and imaging techniques, they found that some parts of the genome—known as TAD-like regions—often form globular shapes in different cells. However, these shapes varied in texture and symmetry, resembling the irregular forms of potatoes found in a supermarket. Features observed in the 3D images suggested that these shapes might influence the activity of nearby genes.

If you picture these clumps of chromatin fiber being roughly in the shape of a potato, we predicted that regions of the genome closer to the surface are more active due to exposure to nearby biochemical signals in the cell nucleus.

Yuk-Lap (Kevin) Yip, Ph.D., Study Senior and Corresponding Author, Professor and Interim Director, Center for Data Sciences, Sanford Burnham Prebys

The researchers hypothesized that, like the tough outer skin of a potato shielding its interior, deeply buried genomic regions might be less accessible to signals that activate gene expression. To explore this idea, they developed a method to measure the distance between specific genomic sites and the inner core of chromatin clusters.

Yichen added, “We used a metric to quantify the ‘coreness’ of a genomic region in a chromatin domain. This measure also allowed us to define the surface and core, and we went on to show that surface regions are more active than core regions.”

“The type of data we can apply this measure to is becoming quite plentiful. There is a lot of potential to study how coreness links to gene activity and disease in different cell types,” stated Yip.

Yip and Li plan to continue their work with the lab of Pier Lorenzo Puri, MD. Their goal is to better understand how the 3D structure of the genome influences the development of muscle stem cells and the progression of muscular dystrophy.