Identifying the genetic 'switches' of bone growth

Tuesday, 25 June, 2024

Identifying the genetic 'switches' of bone growth

Researchers at the University of Geneva (UNIGE) have identified and located 2700 genome sequences that precisely regulate the genes responsible for bone growth, shedding light on one of the major factors influencing the size of individuals in adulthood. Their results can be found in the journal Nature Communications.

Tall or short, our height is largely inherited from our parents. Furthermore, many genetic diseases affect bone growth, the exact cause of which often remains unknown. But genes do not function alone — they are controlled by other sequences in the genome which, like switches, activate or deactivate them as required.

“Short DNA sequences — known as enhancers — give the signal for transcription of DNA into RNA, which is then translated into proteins,” explained Assistant Professor Guillaume Andrey, who led the UNIGE research. “While the genes that regulate bone formation and their location in the genome are already well known, it is not the case for the switches that control them.”

Andrey and his team have developed an innovative experimental technique which makes it possible to obtain mouse embryos carrying a precise genetic configuration from murine stem cells. “In this case,” explained first author Fabrice Darbellay, “our mouse embryos have fluorescent bones that are visible by imaging, enabling us to isolate the cells of interest to us and analyse how the enhancers work during bone development.”

Skeleton of a mouse embryo visible by fluorescence. Image ©Darbellay et al.

The team monitored the activity of chromatin, the structure in which DNA is packaged, in the fluorescent bone cells. Using markers of gene activation, the scientists were able to identify precisely which regulatory sequences came into action to control the genes responsible for building bone. They confirmed their discovery by selectively deactivating 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 to the proper functioning of the gene,” Darbellay said. Of the 2700 switches identified in the mice — among millions of non-coding genetic sequences — 2400 are found in humans.

“Each chromosome is a long strand of DNA,” Andrey said. “Like pearls on a necklace, the enhancers and the genes they control form little balls of DNA on the same chromosomal thread. It is this physical proximity that enables them to interact in such a controlled way. Variations in the activity of these regions could also explain the differences in size between human beings: the activity of bone cells is indeed linked to the size of bones and therefore of individuals.

Moreover, many bone diseases cannot be explained by a mutation affecting the sequence of a known gene. The answer could be found elsewhere, 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 in the genes themselves is the cause of bone disease,” the study authors said. “It is therefore very likely that the number of cases is underestimated, especially when the patients’ genes appear normal.”

Beyond bone disease, failures of these as-yet-little-understood genetic switches could be the cause of many other developmental pathologies.

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