Back to Search
Start Over
p63 establishes epithelial enhancers at critical craniofacial development genes
- Source :
- Science Advances
- Publication Year :
- 2019
- Publisher :
- American Association for the Advancement of Science, 2019.
-
Abstract
- Enhancers at critical craniofacial development genes are established by p63 and enriched for SNPs associated with CL/P.<br />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.
- Subjects :
- Male
Transcription, Genetic
Cleft Lip
Foreskin
Kruppel-Like Transcription Factors
Diseases and Disorders
Biology
Transfection
Polymorphism, Single Nucleotide
Facial Bones
Kruppel-Like Factor 4
03 medical and health sciences
Genetics
Humans
Point Mutation
Craniofacial
Enhancer
Gene
Transcription factor
Research Articles
030304 developmental biology
Epigenomics
0303 health sciences
Multidisciplinary
integumentary system
Tumor Suppressor Proteins
Point mutation
Skull
030305 genetics & heredity
Brain
SciAdv r-articles
Epithelial Cells
DNA-binding domain
Fibroblasts
Up-Regulation
Cell biology
Cleft Palate
stomatognathic diseases
Enhancer Elements, Genetic
HEK293 Cells
sense organs
Sterile alpha motif
Genome-Wide Association Study
Transcription Factors
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 23752548
- Volume :
- 5
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Science Advances
- Accession number :
- edsair.doi.dedup.....a69f30ea03918dd1ba930fdd4c900f54