Cleft lip and palate (CL/P) is the second most common birth defect in the world, reports the Perelman School of Medicine at the University of Pennsylvania, affecting one in 700 live born babies. While its exact cause isn’t well understood, researchers believe it could be the result of a combination of genetics and environment.
The researchers at the Perelman School have found more than 100 genes that could lead to the development of CL/P. They also discovered that genetic variants near these genes are in regions of the genome called enhancers that regulate gene expression to maintain proper cell identity.
The p63 protein plays a role in modulating the expression of genes involved in craniofacial development. The transcription factor p63 guides other molecules to open or close DNA structures in the nucleus called chromatin. This duty of p63 helps enhancers do their job of allowing genes to be expressed into mRNA or not.
Mutations in p63 lead to developmental defects including clefting. Knowledge is limited about p63’s role in craniofacial development due in part to a lack of comparable animal models. But it is now known that p63 binds to and remodels chromatin to coordinate enhancers associated with epithelial cells that are important for palate fusion during development.
“We combined our molecular findings with genome data from colleagues at the University of Bonn who work with genetic data of patients with cleft palates or lips,” said doctoral student Enrique Lin-Shiao. “In the datasets, we found that many of the genes that are highly associated with clefting are located near the enhancer regions what work with p63. This gives us brand new insight into the mechanisms that could lead to disease.”
The researchers identified many new causal candidate genes and the enhancers that regulate them, providing answers to critical questions about CL/P. In the future, they hope that as they delve more into the biology of specific causative genes, new preventions and therapies for a range of craniofacial conditions that include CL/P can be developed.
The study was published by Science Advances.