In mammals, only 3% of the genome makes proteins crucial for life and development. However, genes don’t work alone; they are controlled by other DNA sequences called enhancers, which act like switches to turn genes on or off. Researchers at the University of Geneva found 2,700 enhancers that regulate bone growth genes.
Our height is largely inherited, and many genetic diseases affect bone growth. The cause might lie not in the genes but in the enhancers that activate them. Guillaume Andrey, a researcher at UNIGE, explains that enhancers signal DNA to make RNA, which then makes proteins. While we know where bone growth genes are, the enhancers controlling them are not yet known.
Using a new technique, Andrey’s team created mouse embryos with fluorescent bones to study how enhancers work during bone development. This technique, awarded in 2023, allows precise genetic studies using stem cells.
The team studied the activity of chromatin, where DNA is packaged, in fluorescent bone cells. They identified the specific regulatory sequences controlling bone-building genes using gene activation markers. They confirmed their findings by turning off these enhancers without affecting the genes. This led to a loss of gene activation, proving that the enhancers are crucial for proper gene function, explains Fabrice Darbellay.
The researchers identified 2,700 enhancers in mice and 2,400 also in humans. Enhancers and the genes they control are close together on the same DNA strand, allowing them to interact efficiently, explains Guillaume Andrey. Differences in these regions’ activity could explain why people are different sizes, as bone cell activity affects bone size.
Many bone diseases can’t be explained by gene mutations alone; the cause might be in the non-coding regulatory regions of the genome. Some bone diseases are already known to be caused by enhancer mutations, not genes. This suggests there may be more cases, especially when patients’ genes appear normal. Failures in these genetic switches could also cause other developmental issues.
Journal reference:
- Darbellay, F., Ramisch, A., Lopez-Delisle, L. et al. Pre-hypertrophic chondrogenic enhancer landscape of limb and axial skeleton development. Nature Communications. DOI: 10.1038/s41467-024-49203-2.
