How cells maintain genetic balance with remarkable precision
Researchers from KU Leuven and Erasmus MC (the Netherlands) have shown that cells can compensate for the loss of genes on the X chromosome by increasing the expression of the other gene copy. Surprisingly, this compensation occurs with remarkable precision, on a gene-by-gene basis. The findings help explain how cells maintain balance in their genetic activity, and open new perspectives for research into genetic disorders. The results were published in Nature Communications.
Every healthy human cell contains two copies of each chromosome, but the sex chromosomes are an exception. Sex chromosomes, X and Y in humans, determine biological sex. Typically, individuals with two X chromosomes in their cells are assigned female at birth and individuals with one X and one Y chromosome are assigned male at birth. It is known that in biological females, one copy of the X chromosome is inactivated in their cells. Additionally, all cells (both male and female) increase the activity of their single active X chromosome, a process called X-chromosome upregulation (XCU), to maintain balance with the other chromosomes present in two copies. XCU had been previously described, but its exact workings remained unclear.
A team led by Professor Vincent Pasque (KU Leuven) and Professor Joost Gribnau (Erasmus MC) has now demonstrated that upregulation occurs in a surprisingly refined way—not across the chromosome as a whole, but gene-by-gene. The researchers used mouse stem cells containing two X chromosomes in which parts of one of the two X chromosomes had been selectively removed.
Highly effective balancing system
The team tested whether a specific DNA segment on the X chromosome might detect gene loss and trigger compensation.
“We expected to find a sort of ‘compensation center’ that would balance the chromosome as a whole but that turned out not to be the case,” says Professor Vincent Pasque. “Instead, we observed that individual chromosome regions or genes seem to detect the loss of their counterpart and respond accordingly.”
Secondly, the researchers also tested whether this compensation mechanism is also present in other chromosomes.
“The results show that not only losses on the X chromosome can be compensated by upregulation of their counterpart. It can also occur on other chromosomes, which might be important for instance when a gene is partially silenced due to a mutation,” explains Pasque.
Better understanding of genetic disorders
These findings provide new insights into how cells preserve balance, even when part of the DNA is missing or inactive. This is particularly relevant for understanding congenital conditions such as Turner syndrome, in which one X chromosome is missing, but also for cancer research or in vitro fertilization, where genes or chromosome segments are frequently lost.
“It’s fascinating that cells seem to have an internal ‘scale’ that adjusts gene-by-gene,” says researcher Ryan Allsop (KU Leuven). “That makes the cell more resilient, but also raises new questions about what happens when this mechanism fails. Our results suggest that X chromosomes have a highly effective balancing system to compensate for gene loss or inactivation. For other chromosomes, the compensation may be just enough to keep the cell alive, but not enough to prevent disease.”
“If we can understand why this process works so well on X chromosomes, we may be able to explore potential medical applications for other chromosomes,” Pasque concludes.
More information
The study ‘X-chromosome upregulation operates on a gene-by-gene basis at RNA and protein levels’ by Allsop et al. (DOI: 10.1101/2025.06.18.660324) was published in Nature Communications and was funded by the Research Foundation – Flanders (FWO), KU Leuven, the Pandarome project (Excellence of Science programme), the Oncode Institute, and ZonMw.
This is fundamental research. A breakthrough in (bio)medical research does not automatically translate into a breakthrough in clinical medicine. Before promising research results can lead to new treatments or diagnostic methods, a further development process is required, which may take many years.
This study investigates fundamental biological processes at the level of chromosomes and gene expression. The findings pertain to genetic mechanisms that are typically used to assign a biological sex at birth and do not pertain to or make any statements about the personal experiences, identification or, gender identity of people with sex chromosome variations or, people with differences in sex development.