Your DNA is constantly moving—and it may explain cancer

New findings from his lab show that the genome's 3D organization is not fixed. Instead, it is constantly shifting. By studying different human cell types, the researchers discovered that DNA repeatedly unfolds and refolds at varying speeds across the genome, directly affecting how genes are turned on or off.

The study, published in Nature Genetics and supported by federal grants and private funding, points to potential ways to target harmful folding patterns linked to disease.

"There are six billion base pairs in your genome, and in the last decade we've been learning about the molecular machines that fold and organize that massive amount of information," says Dixon, senior author of the study and associate professor and holder of the Helen McLoraine Developmental Chair at Salk. "What's interesting is that this folding doesn't just happen once and then the genome stays put -- it seems to be constantly unfolding and refolding. Our study gives us a better idea of where and how often the genome is doing this, which ultimately adds to our understanding of those molecular machines, and, in turn, what may be going on when they dysfunction during cancers or developmental disorders."

DNA Packaging: Loops, Proteins, and Organization

Each human cell contains about two meters of DNA, which carries the instructions needed to build proteins and control cellular processes. Within this long strand are tens of thousands of genes that guide how cells function.

To fit inside the tiny nucleus of a cell, DNA must be carefully organized. At the same time, it must remain flexible enough to allow certain genes to be accessed while others stay inactive. Cells achieve this balance by forming loops in the DNA. These loops are created by a protein complex called cohesin, working with another protein, NIPBL, which helps move cohesin along the DNA strand.

Scientists have recently learned that these loops are not permanent. They continuously form and break apart, raising new questions about how often this happens and whether some regions of DNA are more active than others.

DNA Motion and Gene Activity

"Current data around the spatial organization of the genome suggest that genome folding has little impact on gene expression -- but we thought, perhaps we just aren't looking at it in the right way," says first author Tessa Popay, PhD, a postdoctoral researcher in Dixon's lab. "By specifically disrupting folding dynamics, we were able to identify the aspects of spatial genome organization that contribute to gene regulation and expression."

To investigate this, the team reduced levels of NIPBL in human retinal pigment epithelial (RPE-1) cells. Without NIPBL, cohesin could not move effectively along DNA, preventing new loops from forming. As a result, the genome began to unfold, but not evenly. Some regions changed quickly, while others took hours.

The researchers noticed a clear pattern. More stable regions tended to contain inactive genes, while rapidly changing regions were linked to genes that were actively being used.

Cell Identity and the Role of Genome Dynamics

To see how these changes affect different cell types, the team studied heart cells and neurons created from human induced pluripotent stem cells (iPSCs). They found that dynamic DNA folding was especially important in regions tied to each cell's specific role. Genes critical for heart function behaved this way in heart cells, while neuron-related genes did the same in brain cells.

This suggests that the constant reshaping of DNA helps cells maintain their identity. In other words, the genome's movement may help a cell stay true to its function.

"One thing this appears to suggest is that the continuous folding and unfolding of our genome may be particularly important for helping a cell 'remember' who it is supposed to be by preserving expression of genes that are unique to different cell types," says Popay.

Researchers believe that repeated formation of DNA loops may reinforce these identity-defining gene patterns, repeatedly connecting important regions and strengthening their activity.

Implications for Cancer and Developmental Disorders

Although many questions remain, the findings help explain how errors in genome folding can lead to disease.

"These genome folding machineries tightly control cell identity in every cell, so it actually makes a lot of sense that when we see mutations in them, we get these syndromic conditions like Cornelia de Lange syndrome that impact different parts of the body in different ways," says Dixon. "And cancer is potentially exploiting that same principle, changing where in the genome these dynamics are more important to manipulate cell identity and encourage uncontrolled growth."

By confirming that the genome's 3D structure plays a major role in gene activity, this research helps link DNA organization to disease. It also opens the door to future treatments aimed at correcting harmful folding patterns in conditions such as cancer and developmental disorders.

Study Contributors and Funding

The study also included Ami Pant, Femke Munting, Morgan Black, and Nicholas Haghani of Salk, along with Melodi Tastemel of UC San Diego.

Funding was provided by the National Institutes of Health (U01-CA260700, S10-OD023689, S10-OD034268, P30-CA014195, P30-AG068635, P01-AG073084-04, P30-AG062429), Salk Excellerators Fellowship, Rita Allen Foundation, Pew Charitable Trusts, Howard and Maryam Newman Family Foundation, Helmsley Charitable Trust, Chapman Foundation, Waitt Foundation, American Heart Association Allen Initiative, and California Institute for Regenerative Medicine.