A mere 3% of the mammalian genome is composed of coding genes, which are transcribed into proteins crucial for biological functions and in-utero development. However, genes operate under the control of enhancers, non-coding sequences that act like switches to activate or deactivate them. Researchers from the University of Geneva (UNIGE) have pinpointed 2700 such enhancers that specifically regulate genes involved in bone growth. This finding, detailed in Nature Communications, elucidates a significant factor influencing adult height and potential causes of bone malformations.
The Hidden Regulators of Bone Growth
Height is largely inherited, and numerous genetic diseases impact bone growth, often with unknown causes. The research led by Guillaume Andrey, assistant professor at the UNIGE Faculty of Medicine and the Geneva Institute of Genetics and Genomics (IGE3), suggests that the answers might lie not in the genes but in other genomic regions that activate them. Andrey explains, "Short DNA sequences—known as enhancers—give the signal for transcription of DNA into RNA, which is then translated into proteins. 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.”
Fluorescent Bone Cells and Enhancer Activity
Andrey and his team developed an advanced experimental technique to explore these enhancers. This technique was recognized with the Swiss 3R Competence Centre Prize in 2023 and involves creating mouse embryos with specific genetic configurations from murine stem cells. "Our mouse embryos have fluorescent bones that are visible by imaging, enabling us to isolate the cells of interest and analyze how the enhancers work during bone development," explains Fabrice Darbellay, a post-doctoral researcher in Andrey’s laboratory and the first author of this study.
The team monitored chromatin activity, specifically in the fluorescent bone cells. By using markers of gene activation, they identified which regulatory sequences were active in controlling bone-building genes. They further validated their findings by selectively deactivating these enhancers without affecting the coding genes. "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 notes.
Physical Proximity in Chromosomes
Among the 2700 enhancers identified in mice, 2400 are also present in humans. "Each chromosome is a long strand of DNA. 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," explains Andrey. Variations in these regions' activity could explain differences in human height since bone cell activity is linked to bone size and, consequently, individual height.
Implications for Bone Diseases
Many bone diseases remain unexplained by mutations in known gene sequences. The study suggests that mutations in enhancers, rather than in the genes themselves, might be the cause. "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. It is therefore very likely that the number of cases is underestimated, especially when the patients’ genes appear normal," the authors explain. Failures in these genetic switches might also underlie various other developmental pathologies.
The Hidden Regulators of Bone Growth
Height is largely inherited, and numerous genetic diseases impact bone growth, often with unknown causes. The research led by Guillaume Andrey, assistant professor at the UNIGE Faculty of Medicine and the Geneva Institute of Genetics and Genomics (IGE3), suggests that the answers might lie not in the genes but in other genomic regions that activate them. Andrey explains, "Short DNA sequences—known as enhancers—give the signal for transcription of DNA into RNA, which is then translated into proteins. 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.”
Fluorescent Bone Cells and Enhancer Activity
Andrey and his team developed an advanced experimental technique to explore these enhancers. This technique was recognized with the Swiss 3R Competence Centre Prize in 2023 and involves creating mouse embryos with specific genetic configurations from murine stem cells. "Our mouse embryos have fluorescent bones that are visible by imaging, enabling us to isolate the cells of interest and analyze how the enhancers work during bone development," explains Fabrice Darbellay, a post-doctoral researcher in Andrey’s laboratory and the first author of this study.
The team monitored chromatin activity, specifically in the fluorescent bone cells. By using markers of gene activation, they identified which regulatory sequences were active in controlling bone-building genes. They further validated their findings by selectively deactivating these enhancers without affecting the coding genes. "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 notes.
Physical Proximity in Chromosomes
Among the 2700 enhancers identified in mice, 2400 are also present in humans. "Each chromosome is a long strand of DNA. 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," explains Andrey. Variations in these regions' activity could explain differences in human height since bone cell activity is linked to bone size and, consequently, individual height.
Implications for Bone Diseases
Many bone diseases remain unexplained by mutations in known gene sequences. The study suggests that mutations in enhancers, rather than in the genes themselves, might be the cause. "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. It is therefore very likely that the number of cases is underestimated, especially when the patients’ genes appear normal," the authors explain. Failures in these genetic switches might also underlie various other developmental pathologies.