Researchers find genetic mechanism that triggers cleft lip and palate
BONN, Germany/PHILADELPHIA, US: It has long been known that the gene TP63 can contribute to the development of cleft lip and palate, but the exact process has been unclear. A joint study by the universities of Bonn and Pennsylvania has now clarified how this mechanism works.
In Europe, about one in 500 babies are born with a cleft lip and palate. The cause is a developmental disorder in the first weeks of embryonic development. As a result, parts of the face or palate do not grow together as normal.
It has long been known that mutations of the TP63 gene can trigger particularly severe forms of this disorder. Those affected suffer not only from cleft formation in the facial area but also from malformations of the extremities and diseases of the skin, hair and teeth. Originally, it was assumed that TP63 only plays a role in the development of this syndromic form of cleft lip and palate.
“In the last two years, however, there has been increasing evidence that this is not the case,” said co-author Dr Kerstin Ludwig from the Institute of Human Genetics at the University Hospital of Bonn. “In our work, we were able to show for the first time that TP63 actually represents a link between the syndromic and the isolated form and how it interferes with facial development.”
Researchers at the University of Pennsylvania have succeeded in programming human cells to become facial cells in culture. This enabled the team to analyse the effect of TP63 on this particular cell type. This data was then combined by the Bonn researchers with genetic data of large patient cohorts. “We were able to show that TP63 increases the activity of a number of genes that play a role in the development of isolated forms of cleft lip and palate,” said Ludwig.
Furthermore, TP63 changes the structure of the chromatin—the complex consisting of DNA and various proteins. Normally, the chromatin thread forms a compact bundle in the cell nucleus. However, when TP63 attaches to the thread, the ball loosens slightly in this area. Together with other modifications, this can lead to the increased reading of a specific gene in this region.
“According to current knowledge, TP63 regulates several thousand locations in our genome in this way,” said co-author Dr Julia Welzenbach from the University of Bonn. “Among them are 17 which, as we already know from large genetic studies, are involved in the formation of scissures and a large number of other regions whose involvement was previously unknown.”
The large number of regions activated by TP63 shows how important this gene is in humans. If its function is severely impaired by a mutation, this defect usually affects a large number of organs. This explains why TP63 was originally only associated with the syndromic form of cleft lip and palate. “In the case of the non-syndromic form, however, its disturbing activity is limited to developing facial cells,” said Ludwig.
The newly established cell system provides scientists with a tool with which they can investigate the biological causes of this developmental disorder in more detail. “For example, we could test the effect of different environmental factors on TP63 activity in facial cells,” stated Ludwig. It is known that environmental influences can increase the risk of facial malformation. Therefore, in the long term, such tests might lead to recommendations for better individual prophylaxis, applying in particular to families which have a genetic predisposition.
The study, titled “p63 establishes epithelial enhancers at critical craniofacial development genes”, was published in the May 2019 issue of Science Advances.