Genome-wide Chromatin Mapping Defines AP2α in the Etiology of Craniofacial Disorders

Abstract

Objective

The aim of this study is to identify direct AP2α target genes implicated in craniofacial morphogenesis.

Design

AP2α, a product of the TFAP2A gene, is a master regulator of neural crest differentiation and development. AP2α 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-oculofacial syndrome characterized by dysmorphic facial features including cleft or pseudocleft lip/palate. We hypothesize that AP2α primes a distinctive group of genes associated with NC development. Human promoter ChIP-chip arrays were used to define chromatin regions bound by AP2α in neural crest progenitors differentiated from human embryonic stem cells.

Results

High-confidence AP2α-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 AP2α consensus sequence.

Conclusions

Knowledge of noncoding SNPs in the genomic loci occupied by AP2α provides an insight into the regulatory mechanisms underlying craniofacial development.

Keywords

ChIP-chip chromatin immunoprecipitation craniofacial morphogenesis neural crest orofacial clefts single-nucleotide polymorphism TFAP2a

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