title: Identification of a face enhancer reveals direct regulation of LIM homeobox 8 (Lhx8) by wingless-int (WNT)/β-catenin signaling.
abstract: Development of the mammalian face requires a large number of genes that are expressed with spatio-temporal specificity, and transcriptional regulation mediated by enhancers plays a key role in the precise control of gene expression. Using chromatin immunoprecipitation for a histone marker of active enhancers, we generated a genome-wide map of candidate enhancers from the maxillary arch (primordium for the upper jaw) of mouse embryos. Furthermore, we confirmed multiple novel craniofacial enhancers near the genes implicated in human palate defects through functional assays. We characterized in detail one of the enhancers (Lhx8_enh1) located upstream of Lhx8, a key regulatory gene for craniofacial development. Lhx8_enh1 contained an evolutionarily conserved binding site for lymphoid enhancer factor/T-cell factor family proteins, which mediate the transcriptional regulation by the WNT/β-catenin signaling pathway. We demonstrated in vitro that WNT/β-catenin signaling was indeed essential for the expression of Lhx8 in the maxillary arch cells and that Lhx8_enh1 was a direct target of the WNT/β-catenin pathway. Together, we uncovered a molecular mechanism for the regulation of Lhx8, and we provided valuable resources for further investigation into the gene regulatory network of craniofacial development.
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York 10010 and.
authors.forename: André
authors.initials: A
authors.lastname: Landin Malt
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York 10010 and.
authors.forename: Jeffry M
authors.initials: JM
authors.lastname: Cesario
authors.affiliation: Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York 10016.
authors.forename: Zuojian
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York 10016.
authors.forename: Stuart
authors.initials: S
authors.lastname: Brown
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York 10010 and. Electronic address: jj78@nyu.edu.
authors.forename: Juhee
authors.initials: J
authors.lastname: Jeong
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001934:Branchial Region / Q000196:embryology / Q000378:metabolism; D002460:Cell Line; D002874:Chromosome Mapping; D016384:Consensus Sequence; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D006657:Histones / Q000378:metabolism; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D008437:Maxilla / Q000196:embryology / Q000378:metabolism; D008648:Mesoderm / Q000196:embryology / Q000378:metabolism; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010159:Palate / Q000002:abnormalities; D061251:Primary Cell Culture; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D006657:Histones; C112960:LIM homeobox protein 8; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors
keywords: ChIP Sequencing (ChIP-seq); Craniofacial Development; First Pharyngeal Arch; Transcription Enhancer; Transcription Factor; Wnt Pathway