Scientists identify genetic 'switches' to bone growth

UNIGE scientists have identified the genetic sequences that regulate the activity of genes responsible for bone growth.

In mammals, only 3% of the genome is made up of coding genes which, transcribed into proteins, ensure the biological functions of the organism and the in utero development of future individuals. But genes don't work alone. They are controlled by other sequences in the genome, called enhancers, which, like switches, turn them on or off as needed.

A team from the University of Geneva (UNIGE) has identified and located 2,700 activators, among millions of non-coding genetic sequences, which precisely regulate the genes responsible for bone growth.

This discovery highlights one of the major factors influencing the height of individuals in adulthood, and explains why their failure could be the cause of certain bone malformations. The results are published in Natural communications.

Whether large or small, our height is largely inherited from our parents. In addition, many genetic diseases affect bone growth, the exact cause of which often remains unknown. What if the explanation could be found not in the genes themselves, but in other parts of the genome responsible for their activation?

Guillaume Andrey, assistant professor in the Department of Genetic Medicine and Development of the Faculty of Medicine of UNIGE and the Institute of Genetics and Genomics of Geneva (IGE3), who led this research, explains: “Short sequences of DNA, called activators, give the transcription signal from DNA to RNA, which is then translated into proteins. Although the genes that regulate bone formation and their location in the genome are already well known, this is not the case for the switches that control them.

Fluorescent bones

Andrey and his team have developed an innovative experimental technique, rewarded in 2023 with the Swiss 3R Competence Center Prize, which makes it possible to obtain mouse embryos carrying a precise genetic configuration from murine stem cells.

“In this case, our mouse embryos have fluorescent bones, visible in imaging, which allows us to isolate the cells that interest us and to analyze the functioning of activators during bone development,” explains Fabrice Darbellay, researcher. postdoctoral fellow at Professor Andrey's University. laboratory and first author of this work.

The team monitored the activity of chromatin, the structure in which DNA is packaged, particularly in fluorescent bone cells. Using gene activation markers, scientists were able to precisely identify which regulatory sequences came into action to control the genes responsible for bone building. They then confirmed their discovery by selectively disabling the enhancers without affecting the coding gene.

“We then observed a loss of activation of the genes in question, which indicates both that we had identified the right switches and that their role is indeed crucial in the proper functioning of the gene,” explains Darbellay.

Three-dimensional mapping

Of the 2,700 switches identified in mice, 2,400 are found in humans. “Each chromosome is a long strand of DNA. Like beads on a necklace, enhancers and the genes they control form little balls of DNA on the same chromosomal thread. It is this physical proximity that allows them to interact in such a controlled way,” Andrey explains.

Variations in the activity of these regions could also explain the differences in size between human beings: the activity of bone cells is in fact linked to the size of bones and therefore of individuals.

Additionally, many bone diseases cannot be explained by a mutation affecting the sequence of a known gene. The answer could be found elsewhere, and more precisely in the non-coding but regulatory regions of the genome.

“There are already a few documented cases where a mutation in the switches rather than the genes themselves causes bone disease. So it is very likely that the number of cases is underestimated, especially when the “Patients' genes appear normal.” explain the authors. And beyond bone diseases, failures of these different genetic switches, still poorly understood, could be the cause of numerous other developmental pathologies.