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Developmental Biology - Cleft Lip/Palate
World's 2nd Most Common Birth Defect
One hundred new genes could lead to the development of CL/P...
Cleft lip and palate (CL/P) is the second most common birth defect in the world, affecting 1 in 700 live born babies. While the exact cause of CL/P is not well understood, investigators think it could be the result of a combination of genetics and environment.
Cleft lip and palate are splits in the upper lip, the roof of the mouth, or both. This happens when cells in a baby's face and mouth don't fuse properly during early development. The result of a partial fusion, or no fusion at all, leaves a cleft.
In a new study published today in Science Advances, researchers from the Perelman School of Medicine at the University of Pennsylvania found more than 100 new genes that could lead to the development of CL/P. The team discovered genetic variants near these genes are in regions of the genome called "enhancers," which regulate expression of genes to maintain proper cell identity.
Enrique Lin-Shiao, a doctoral student in the lab of Shelley L. Berger, PhD, the Daniel S. Och University Professor and director of the Penn Epigenetics Institute, described the role of the protein p63 in modulating 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 human p63 lead to an array of developmental defects, including clefting. Knowledge is limited about p63's role in human craniofacial development due in part to a lack of comparable animal models. However, now it is known that p63 binds to and remodels chromatin to coordinate enhancers associated with epithelial cells that are important for the fusion of the palate during development.
Acording to Enrique Lin-Shiao: "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. In the datasets, we found many of the genes highly associated with clefting are located near enhancer regions that work with p63. This gives us brand new insight into the mechanisms that could lead to disease."
The team identified many new causal candidate genes and the enhancers that regulate them, providing answers to critical questions about CL/P. In the future, the team hopes 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.
Abstract
The transcription factor p63 is a key mediator of epidermal development. Point mutations in p63 in patients lead to developmental defects, including orofacial clefting. To date, knowledge on how pivotal the role of p63 is in human craniofacial development is limited. Using an inducible transdifferentiation model, combined with epigenomic sequencing and multicohort meta-analysis of genome-wide association studies data, we show that p63 establishes enhancers at craniofacial development genes to modulate their transcription. Disease-specific substitution mutation in the DNA binding domain or sterile alpha motif protein interaction domain of p63, respectively, eliminates or reduces establishment of these enhancers. We show that enhancers established by p63 are highly enriched for single-nucleotide polymorphisms associated with nonsyndromic cleft lip ± cleft palate (CL/P). These orthogonal approaches indicate a strong molecular link between p63 enhancer function and CL/P, illuminating molecular mechanisms underlying this developmental defect and revealing vital regulatory elements and new candidate causative genes.
Authors
Enrique Lin-Shiao, Yemin Lan, Julia Welzenbach, Katherine A. Alexander, Zhen Zhang, Michael Knapp, Elisabeth Mangold, Morgan Sammons, Kerstin U. Ludwig and Shelley L. Berger.
Acknowledgements
This work was funded by grants from the National Institutes of Health (R01 CA078831, F31 GM123744-01, F32 12461842, R15GM128049), the German Research Council, and the German Research Foundation.
Coauthors on the study are Yemin Lan, Julia Welzenbach, Katherine A. Alexander, Zhen Zhang, and Morgan Sammons, all from Penn, as well as Michael Knapp, Elisabeth Mangold, and Kerstin U. Ludwig, from the University of Bonn, Germany.
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania(founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise.
The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $425 million awarded in the 2018 fiscal year.
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May 13 2019 Fetal Timeline Maternal Timeline News
Types of cleft lips: (1) Unilateral: on one side (2) Bilateral: on both sides
(3) Complete: extends all the way into the nostril (4) Incomplete: does not extend up into the nostril (5)Isolated: cleft lip without a cleft palate.
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