Craniofacial Birth Defects: It’s the Regulation, Not the Genes

Close up of infant holding its foot.
Image by Daniel Nebreda from Pixabay.

UConn Health assistant professor of genetics and genome sciences Justin Cotney has received nearly $2 million from the National Institutes of Health to study the role of gene regulatory elements in the incidence of craniofacial abnormalities.

Craniofacial abnormalities are some of the most common birth defects in the world. This category includes cleft lips or palates and misshapen skulls.

Previous research on craniofacial abnormalities has shown there is a definitive genetic link, but it isn’t quite so simple as inheriting the gene for a trait, like blue eyes. The key to understanding the genetic factors at play in craniofacial abnormalities lies in the regulatory elements encoded in our DNA.

Regulatory elements make up a much larger portion of our genome than our actual genes. These elements determine how and when a gene is expressed.

“It’s like a thermostat or a dimmer switch that can dial in the level of a gene under a certain cell’s parameters,” Cotney explains.

Regulatory elements are inherited from our parents with our entire genetic code and work similarly to genes. Even if neither parent has craniofacial abnormalities, they could both carry defective copies of the regulatory elements that direct craniofacial development which their child could inherit.

Cotney and his team have previously published a map of regulatory elements that are likely important for normal craniofacial development. However, the cell types that are using a specific element and which gene a regulator element controls remain unknown.

“First, we have to identify the region of the genome that is active when the face is being built,” Cotney says. “We get a snapshot of all that information by looking at what is being used to build the face.”

Cotney and his team will rank the importance of the regulatory elements active during their time frame by the number of cells that are using that stretch of DNA. This will allow the researchers to experiment strategically rather than wading through tens of thousands of DNA sequences.

“We can’t yet look at DNA sequences and know if something is a regulatory element, so we need to narrow down the number of sequences we’re looking at without experimentation or biochemical manipulation,” Cotney says.

The UConn Health team is able to identify these elements at a single cell level thanks to a technological collaboration with other University of Connecticut partners.

“We are utlizing new technology that has been enabled here by a collaboration between UConn, UConn Health, and The Jackson Laboratory for Genomic Medicine,” Cotney says. “If that technology wasn’t available, we wouldn’t be able to do this.”

Once the researchers identify the cell types where regulatory elements are active and the genes they target during craniofacial development, they will be systematically removed or altered to identify what effect they have on development, providing a clearer picture of what determines the occurrence of craniofacial abnormalities.

This research could provide a more accurate way to assess a family’s risk of having children born with craniofacial abnormalities. The team is hopeful that their work could also someday lead to future studies to identify a treatment to reduce the occurrence of craniofacial abnormalities, much like folic acid. This small molecule found in many foods has been recommended by physicians since the 1980s to reduce the risk of birth defects.

Cotney received his Ph.D. in genetics and molecular biology from Emory University. He is the associate director for the UConn Health graduate program in genetics and developmental biology. His research focuses on the effects of gene expression and regulatory functions on mammalian development and human disease as well as how these elements evolve.

This project is NIH Grant No.: 1 R01 DE028945-01

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