title: Fine tuning of craniofacial morphology by distant-acting enhancers.
abstract: The shape of the human face and skull is largely genetically determined. However, the genomic basis of craniofacial morphology is incompletely understood and hypothesized to involve protein-coding genes, as well as gene regulatory sequences. We used a combination of epigenomic profiling, in vivo characterization of candidate enhancer sequences in transgenic mice, and targeted deletion experiments to examine the role of distant-acting enhancers in craniofacial development. We identified complex regulatory landscapes consisting of enhancers that drive spatially complex developmental expression patterns. Analysis of mouse lines in which individual craniofacial enhancers had been deleted revealed significant alterations of craniofacial shape, demonstrating the functional importance of enhancers in defining face and skull morphology. These results demonstrate that enhancers are involved in craniofacial development and suggest that enhancer sequence variation contributes to the diversity of human facial morphology.
authors.affiliation: Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Catia
authors.initials: C
authors.lastname: Attanasio
authors.forename: Alex S
authors.initials: AS
authors.lastname: Nord
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Zhu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Blow
authors.forename: Zirong
authors.initials: Z
authors.lastname: Li
authors.forename: Denise K
authors.initials: DK
authors.lastname: Liberton
authors.forename: Harris
authors.initials: H
authors.lastname: Morrison
authors.forename: Ingrid
authors.initials: I
authors.lastname: Plajzer-Frick
authors.forename: Amy
authors.initials: A
authors.lastname: Holt
authors.forename: Roya
authors.initials: R
authors.lastname: Hosseini
authors.forename: Sengthavy
authors.initials: S
authors.lastname: Phouanenavong
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Akiyama
authors.forename: Malak
authors.initials: M
authors.lastname: Shoukry
authors.forename: Veena
authors.initials: V
authors.lastname: Afzal
authors.forename: Edward M
authors.initials: EM
authors.lastname: Rubin
authors.forename: David R
authors.initials: DR
authors.lastname: FitzPatrick
authors.forename: Bing
authors.initials: B
authors.lastname: Ren
authors.forename: Benedikt
authors.initials: B
authors.lastname: Hallgrímsson
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.forename: Axel
authors.initials: A
authors.lastname: Visel
mesh_terms: D000818:Animals; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000473:pathology; D004742:Enhancer Elements, Genetic / Q000235:genetics / Q000502:physiology*; D044127:Epigenesis, Genetic; D005145:Face / Q000002:abnormalities / Q000033:anatomy & histology*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D008445:Maxillofacial Development / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D017384:Sequence Deletion; D012886:Skull / Q000002:abnormalities / Q000033:anatomy & histology / Q000254:growth & development*