title: Long-range enhancers regulating Myc expression are required for normal facial morphogenesis.
abstract: Cleft lip with or without cleft palate (CL/P) is one of the most common congenital malformations observed in humans, with 1 occurrence in every 500-1,000 births. A 640-kb noncoding interval at 8q24 has been associated with increased risk of non-syndromic CL/P in humans, but the genes and pathways involved in this genetic susceptibility have remained elusive. Using a large series of rearrangements engineered over the syntenic mouse region, we show that this interval contains very remote cis-acting enhancers that control Myc expression in the developing face. Deletion of this interval leads to mild alteration of facial morphology in mice and, sporadically, to CL/P. At the molecular level, we identify misexpression of several downstream genes, highlighting combined impact on the craniofacial developmental network and the general metabolic capacity of cells contributing to the future upper lip. This dual molecular etiology may account for the prominent influence of variants in the 8q24 region on human facial dysmorphologies.
authors.affiliation: Developmental Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
authors.forename: Veli Vural
authors.initials: VV
authors.lastname: Uslu
authors.affiliation: Developmental Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
authors.forename: Massimo
authors.initials: M
authors.lastname: Petretich
authors.affiliation: Developmental Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ruf
authors.affiliation: Developmental Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Langenfeld
authors.affiliation: European Bioinformatics Institute-European Molecular Biology Laboratory (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Nuno A
authors.initials: NA
authors.lastname: Fonseca
authors.affiliation: European Bioinformatics Institute-European Molecular Biology Laboratory (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Marioni
authors.affiliation: Developmental Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
authors.forename: François
authors.initials: F
authors.lastname: Spitz
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D002971:Cleft Lip / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002972:Cleft Palate / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005145:Face / Q000503:physiopathology*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009024:Morphogenesis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger