Foxc1 establishes enhancer accessibility for craniofacial cartilage differentiation.

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Publication Year:
2021
Authors:
PubMed ID:
33501917
Public Summary:
When our bodies form cartilage, a key player is a protein called Sox9, which is involved in various processes beyond just making bones. But how Sox9 and other important factors actually get to the right places in our skeleton during development has been a mystery. In a study using zebrafish, scientists examined how specific parts of DNA that are associated with cartilage become accessible during the development of cartilage-producing cells. They discovered that these regions of DNA become available for use at different times. Interestingly, the regions that become active after certain cells have already moved to where they're needed in the body have specific signals for Sox9 and a group of proteins called Fox. In zebrafish that were missing certain Fox proteins, there was a decrease in the availability of these DNA regions in cartilage-producing cells. This change seemed to affect the development of facial cartilages in these fish, leading to the loss of certain parts of the face. Further experiments in zebrafish confirmed that many of these Fox-dependent DNA regions play a role in boosting the activity of genes in specific parts of facial cartilages at different stages of development. In summary, this study reveals that a group of proteins, including Fox, helps make sure that the right genes are accessible for building cartilage in the face. Understanding this process could be important for improving our knowledge of skeletal development and potential future therapies.
Scientific Abstract:
The specification of cartilage requires Sox9, a transcription factor with broad roles for organogenesis outside the skeletal system. How Sox9 and other factors gain access to cartilage-specific cis-regulatory regions during skeletal development was unknown. By analyzing chromatin accessibility during the differentiation of neural crest cells into chondrocytes of the zebrafish head, we find that cartilage-associated chromatin accessibility is dynamically established. Cartilage-associated regions that become accessible after neural crest migration are co-enriched for Sox9 and Fox transcription factor binding motifs. In zebrafish lacking Foxc1 paralogs, we find a global decrease in chromatin accessibility in chondrocytes, consistent with a later loss of dorsal facial cartilages. Zebrafish transgenesis assays confirm that many of these Foxc1-dependent elements function as enhancers with region- and stage-specific activity in facial cartilages. These results show that Foxc1 promotes chondrogenesis in the face by establishing chromatin accessibility at a number of cartilage-associated gene enhancers.