Penn research into Friedreich’s ataxia reveals how DNA folding can silence a key gene
A study uncovers how a balance between gene activity and DNA folding determines where genes sit in the nucleus—and how misplacement contributes to the neurodegenerative and cardiac disorder
Researchers have uncovered a fundamental rule that governs how genes are physically arranged inside the cell nucleus, and how disruptions to that organization can contribute to human disease. Researchers at the Perelman School of Medicine at the University of Pennsylvania found that a balance between gene activity and the cellular machinery that folds and organizes DNA determines whether genes are pushed to the edge of the nucleus, where they are often silenced.
In the study, published today in Molecular Cell, the multidisciplinary team shows that this mechanism is disrupted in Friedreich’s ataxia (FRDA), a rare inherited neurodegenerative and cardiac disorder, and that re-tuning this balance can partially restore activity of the disease-causing gene.
“This work shows that it’s not an either‑or situation,” said Rajan Jain, MD, the William Wikoff Smith Associate Professor of Cardiovascular Research, and senior author of the study. “Gene activity and the machinery that folds DNA work together like adjustable dials to determine where genes live inside the nucleus and whether they can function properly.”
Why gene location matters
Inside every cell nucleus, DNA is not randomly packed. Instead, chromosomes are carefully arranged in three‑dimensional space. Genes located near the nuclear lamina—a supportive structure lining the inner edge of the nucleus—are typically less active, while genes positioned more toward the nuclear interior are more likely to be turned on. For years, scientists observed this pattern, but it has been unclear whether gene activity controls location, or whether location controls gene activity.
The researchers focused on two key processes: transcription, which is how a gene is read to make RNA, and cohesin, a protein complex that helps organize DNA by folding it into loops and bringing different parts of the genome together in three-dimensional space.
Using CRISPR-based tools, the team showed that turning down transcription caused certain genes to move toward the nuclear edge—a region associated with gene silencing. At the same time, overactive cohesin — or organizing DNA into the wrong places in the nucleus— pushed genes to the outer edges of the nucleus and shut them down. Researchers found that restoring transcription and dialing back cohesin activity could pull genes back toward the nuclear interior and revive their expression.
The researchers describe this interplay as a “rheostat”, similar to a dimmer switch, that continuously adjusts gene positioning and activity rather than flipping genes strictly on or off.
Impacts on Friedreich’s ataxia
The team chose Friedreich’s ataxia as a disease model because its root cause involves the unusual silencing of a single, well‑studied gene: FXN, which encodes the protein frataxin. In people with FRDA, a repeated stretch of DNA within the FXN gene interferes with gene activity, dramatically lowering frataxin levels and leading to devastating neurological and cardiac symptoms.
When the team examined FXN in cells from FRDA patients, they found it more frequently at the nuclear edge, an abnormal placement they believed may reinforce its low gene activity. They reduced cohesin in FRDA cells and the FXN gene moved away from the nuclear edge and back toward the interior. This shift was accompanied by a significant increase in FXN levels, even though the underlying DNA mutation remained.
“These results suggest that gene silencing in Friedreich’s ataxia is reinforced by where the gene sits in the nucleus,” said Ashley Karnay, PhD, a postdoctoral fellow in Cardiovascular Medicine and Cell & Developmental Biology and the study’s lead author. “By changing that positioning, we can partially restore FXN gene activity in diseased cells.”
While the findings are early and not a treatment, they point to genome organization itself as a contributor to disease and raise the exciting possibility that future therapies could work by changing how the DNA is organized inside the nucleus.
The work was funded by the National Institutes of Health (F31HL16011, T32GM008216, T32HL007843, T32HD083185, R21AG081795, R35HL166663, and U01DA052715), the American Heart Association (24PRE1185932 and 26POST1561633), the Friedreich’s Ataxia Research Alliance, the Burroughs Welcome Foundation, and the W.W. Smith Charitable Trust.