Genetic control of bone growth

In mammals, only 3% of the genome makes proteins crucial for life and development. However, genes do not work alone; they are controlled by other DNA sequences called enhancers, which act as 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 may not lie in the genes, but in the enhancers that activate them. Guillaume Andrey, a researcher at UNIGE, explains that enhancers signal DNA to create RNA, which then produces proteins. While we know where the bone growth genes are, the enhancers that control them are not yet known.

Using a new technique, Andrey’s team created mouse embryos with fluorescent bones to study how the enhancers work during bone development. This technique, given 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 that control 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 enhancers are essential for proper gene function, explains Fabrice Darbellay.

The researchers identified 2,700 enhancers in mice and 2,400 in humans. The enhancers and the genes they control are close together on the same DNA strand, allowing them to interact efficiently, explains Guillaume Andrey. Differences in the activity of these regions may explain why people have different sizes, as the activity of bone cells affects bone size.

Many bone diseases cannot be explained by gene mutations alone; the cause may be in non-coding regulatory regions of the genome. Some bone diseases are now known to be caused by enhancer mutations, not genes. This suggests that there may be more cases, especially when patients’ genes appear normal. Failures in these genetic changes can also cause other developmental problems.

Journal reference:

1. Darbellay, F., Ramisch, A., Lopez-Delisle, L. et al. Pre-hypertrophic chondrogenic amplifier landscape of limb and axial skeleton development. Nature Communications. DOI: 10.1038/s41467-024-49203-2.