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Fine Tuning of Craniofacial Morphology by Distant-Acting Enhancers

Research output: Contribution to journalArticle

  • Catia Attanasio
  • Alex S Nord
  • Yiwen Zhu
  • Matthew J Blow
  • Zirong Li
  • Denise K Liberton
  • Harris Morrison
  • Ingrid Plajzer-Frick
  • Amy Holt
  • Roya Hosseini
  • Sengthavy Phouanenavong
  • Jennifer A Akiyama
  • Malak Shoukry
  • Veena Afzal
  • Edward M Rubin
  • David R FitzPatrick
  • Bing Ren
  • Benedikt Hallgrímsson
  • Len A Pennacchio
  • Axel Visel

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    Rights statement: Published in final edited form as: Science. Oct 25, 2013; 342(6157): 1241006. doi: 10.1126/science.1241006

    Accepted author manuscript, 2 MB, PDF-document

http://www.sciencemag.org/content/342/6157/1241006.abstract
Original languageEnglish
Article number1241006
Number of pages10
JournalScience
Volume342
Issue number6157
DOIs
StatePublished - 25 Oct 2013

Abstract

Introduction: The shape of the face is one of the most distinctive features among humans, and differences in facial morphology have substantial implications in areas such as social interaction, psychology, forensics, and clinical genetics. Craniofacial shape is highly heritable, including the
normal spectrum of morphological variation as well as susceptibility to major craniofacial birth defects. In this study, we explored the role of transcriptional enhancers in the development of the craniofacial complex. Our study is based on the rationale that such enhancers, which can be hundreds of kilobases away from their target genes, regulate the spatial patterns, levels, and timing of
gene expression in normal development.

Methods: To identify distant-acting enhancers active during craniofacial development, we used chromatin immunoprecipitation on embryonic mouse face tissue followed by sequencing to identify noncoding genome regions bound by the enhancer-associated p300 protein. We used LacZ reporter assays in transgenic mice and optical projection tomography (OPT) to determine three-dimensional expression patterns of a subset of these candidate enhancers. Last, we deleted three of the craniofacial enhancers from the mouse genome to assess their effect on gene expression and craniofacial morphology during development.

Results: We identifi ed more than 4000 candidate enhancer sequences predicted to be active in the developing craniofacial complex. The majority of these sequences are at least partially conserved between humans and mice, and many are located in chromosomal regions associated with normal facial morphology or craniofacial birth defects. Characterization of more than 200 candidate
enhancer sequences in transgenic mice revealed a remarkable spatial complexity of in vivo expression patterns. Targeted deletions of three craniofacial enhancers near genes with known roles in craniofacial development resulted in changes of expression of those genes as well as quantitatively subtle but defi nable alterations of craniofacial shape.

Discussion: Our analysis identifi es enhancers that fi ne tune expression of genes during craniofacial development in mice. These results support that variation in the sequence or copy number of craniofacial enhancers may contribute to the spectrum of facial variation we fi nd in human
populations. Because many craniofacial enhancers are located in genome regions associated with craniofacial birth defects, such as clefts of the lip and palate, our results also offer a starting point for exploring the contribution of noncoding sequences to these disorders.

Research areas

  • Animals, Craniofacial Abnormalities, Enhancer Elements, Genetic, Epigenesis, Genetic, Face, Gene Expression Profiling, Gene Expression Regulation, Developmental, Gene Targeting, Maxillofacial Development, Mice, Mice, Transgenic, Sequence Deletion, Skull

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