Genome-Wide Chromatin Mapping Defines Ap2 Alpha In The Etiology Of Craniofacial Disorders

Objective: The aim of this study is to identify direct AP2 alpha target genes implicated in craniofacial morphogenesis.Design: AP2 alpha, a product of the TFAP2A gene, is a master regulator of neural crest differentiation and development. AP2 alpha is expressed in ectoderm and in migrating cranial neural crest (NC) cells that provide patterning information during orofacial development and generate most of the skull bones and the cranial ganglia. Mutations in TFAP2A cause branchio-oculo-facial syndrome characterized by dysmorphic facial features including cleft or pseudocleft lip/palate. We hypothesize that AP2 alpha primes a distinctive group of genes associated with NC development. Human promoter ChIP-chip arrays were used to define chromatin regions bound by AP2 alpha in neural crest progenitors differentiated from human embryonic stem cells.Results: High-confidence AP2 alpha-binding peaks were detected in the regulatory regions of many target genes involved in the development of facial tissues including MSX1, IRF6, TBX22, and MAFB. In addition, we uncovered multiple single-nucleotide polymorphisms (SNPs) disrupting a conserved AP2 alpha consensus sequence.Conclusions: Knowledge of noncoding SNPs in the genomic loci occupied by AP2 alpha provides an insight into the regulatory mechanisms underlying craniofacial development.