Cutting to the core of how 3D structure shapes gene activity

In biology manuals and beyond, human genome and DNA are generally taught in a single dimension. Although it can be useful for learners to start with the linear presentation of the way in which DNA stretches form genes, this simplification outside underestimates the meaning of the 3D structure of the genome.

To hold in the nucleus of our cells, six DNA feet are rolled up like wire on protein coils called histones. In its excited shape called chromatin, rolled DNA has many loops and tufts. Although it may seem random and disorderly with the unused eye, these Tumbleweed type forms put certain genomic regions in close contact while hosting others.

Problems with this 3D structure are associated with many diseases, including developmental disorders and cancer. Almost 12% of genomic regions in breast cancer cells have engaged problems with their chromatin structure, while other structural problems are known to cause acute cell cell leukemia.

Scientists from Sanford Burnham Prebys and Hong Kong colleagues have published the results of June 27, 2025 Genome biology Demonstrating a new approach to better understand the 3D structure of chromatin and its influence.

The research team has hypothesized that the 3D form of genome regions influences the way the genes are regulated.

“We know that many regions of the genome tend to form what are called domains or tads associated with topologically,” said Kelly Yichen Li, Ph.D., postdoctoral partner in Sanford Burnham Prebys and the main study of the study. “The parts of the genome in these areas can interact more frequently with each other, when they tend to be isolated from the region outside this area.”

The researchers noticed when they took many chromatin images to conduct spatial cartography experiments, TAD type regions of the genome in individual cells tended to take a globular shape, although with the varied bump and spherical irregularity of the selection of potatoes by a supermarket. Certain characteristics of these regions in 3D images suggest that they can influence the function of genes nearby.

“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,” Said Yuk-Lap (Kevin) Yip, Ph.D. Director of the Center for Data Sciences at Sanford Burnham Prebys, and the Senior and corresponding Author of the Manuscript.

Similar to the protection offered by the fibrous skin of a potato potato with its starchy flesh, scientists predicted that the signals promoting the expression of the genes would have more difficulty in reaching the regions of the genome buried near the nucleus of a globular chromatin bundle. To test this, they have developed a method of measuring the proximity of a genomic region with the isolated center of a chromatin tuft.

“We used a metric to quantify the” horn “of a genomic region in a field of chromatin,” said Li. “This measure also allowed us to define the surface and the nucleus, and we have continued to show that the surface regions are more active than the central regions.”

“The type of data to which we can apply this measure becomes quite abundant,” said Yip. “There is a lot of potential to study how the origin is linked to the activity of genes and diseases in different types of cells.”

Yip and Li plan to continue to collaborate with the laboratory of Pier Lorenzo Puri, MD, to advance our understanding of the way in which the 3D structure of the genome affects the development of muscle stem cells and the progression of muscular dystrophy.