In mammals, only a small fraction, about 3%, of the genome is dedicated to coding proteins essential for life and development. However, genes do not operate in isolation; they are governed by other DNA segments known as enhancers. These enhancers function like switches, dictating when genes should be active or inactive. Researchers at the University of Geneva have identified 2,700 enhancers that play a role in regulating genes responsible for bone growth.

Height, a trait largely inherited in humans, and various genetic disorders affecting bone growth may be influenced not just by genes themselves but also by these enhancers that control their activation. Guillaume Andrey, a researcher at UNIGE, explains that enhancers send signals to DNA, prompting the production of RNA, which then translates into proteins. While the locations of bone growth genes are known, their associated enhancers have remained elusive until now.

Using an innovative method, Andrey’s team developed mouse embryos with fluorescent bones to investigate how enhancers function during bone development. This approach, honored with an award in 2023, enables precise genetic studies using stem cells.

By studying the activity of chromatin—where DNA is packaged—in fluorescent bone cells, the researchers pinpointed specific regulatory sequences that govern genes involved in bone formation. They validated their discoveries by deactivating these enhancers, which resulted in diminished gene activation. This experimental outcome underscores the critical role of enhancers in ensuring proper gene function, as explained by Fabrice Darbellay.

The team identified 2,700 enhancers in mice, with a significant overlap of 2,400 enhancers also found in humans. According to Guillaume Andrey, enhancers and their target genes are closely situated on the same DNA strand, facilitating efficient interaction. Variations in the activity of these regions could potentially account for differences in human height, given the influence of bone cell activity on bone size.

Many bone disorders that cannot be solely attributed to gene mutations may originate from defects in the non-coding regulatory regions of the genome. Some bone diseases are already known to result from mutations in enhancers rather than in genes themselves, suggesting there may be additional cases where patients exhibit normal gene sequences. Failures in these genetic switches could also contribute to various developmental abnormalities.