Early in development, a group of migrating cells called cranial neural crest cells go on to form many different parts of the face, including the nose, jaw, ears and throat. To build these structures correctly, genes must switch on in the right cells at the right time. But many of the DNA switches that control those genes sit far away on the genome, and scientists still know little about how genes find and communicate with these distant switches during development.
Researchers in the Rijli group turned to a group of proteins called Polycomb. Polycomb complexes are best known for silencing genes, but over the past decade, evidence has suggested they may also help organize the genome in three dimensions.
Using mouse facial development as a model, the team studied cranial neural crest cells as they migrated and adopted distinct identities. Earlier work from the group had shown that many genes involved in facial development are kept in an intermediate state: repressed by Polycomb, but marked in a way that keeps them ready for rapid activation.
The new work suggests that Polycomb also physically pre-arranges the genome before those genes are turned on. The researchers found that long before the genes became active, Polycomb helped bring them near distant DNA regions that could later help control them, such as enhancers — stretches of DNA that act as gene switches.
Once migrating cells reached their destination and received local developmental signals, those pre-formed structures were reorganized. Genes that needed to turn on broke away from Polycomb-associated networks and formed new contacts with distant enhancers, activating programs needed to shape specific facial structures. When the researchers removed Ezh2, a key Polycomb component, this rewiring failed. Some genes became active in the wrong places, while others could no longer properly connect to their distant enhancers and failed to switch on strongly enough.
The findings may reflect a broader principle in development, because similar Polycomb-organized DNA contacts have already been observed in embryonic stem cells, which give rise to all tissues, says study senior author Filippo Rijli. But, he adds, “it’s not known how the Polycomb-organized DNA contacts switch from to the active conformation.”
His lab is now trying to understand how cells move from this Polycomb-organized state to the active genome folding systems that help genes switch on.
Rijli also speculates that this pre-existing network of contacts may help cells fine-tune when and where they respond to local signals. “By sampling active DNA conformations, cells could create small, localized changes in craniofacial gene activity levels, which may ultimately influence the final shape of the face,” he says.