Identification of conserved skeletal enhancers associated with craniosynostosis risk genes

Author:

He (何璇) Xuan Anita12ORCID,Berenson Anna34,Bernard Michelle15,Weber Chris6,Cook Laura7,Visel Axel789,Fuxman Bass Juan I3,Fisher Shannon1

Affiliation:

1. Department of Pharmacology & Experimental Therapeutics , Boston University, 700 Albany St, W607, Boston, MA 02118 , USA

2. Graduate Program in Biomolecular Medicine , Boston University, 72 East Concord St, Boston, MA 02118 , USA

3. Department of Biology , Boston University, 5 Cummington Mall, Boston, MA 02215 , USA

4. Program in Molecular Biology , Cell Biology, and Biochemistry, Boston University, 5 Cummington Mall, Boston, MA 02215 , USA

5. College of Arts and Sciences , Boston University, 5 Cummington Mall, Boston, MA 02215 , USA

6. Department of Cell and Developmental Biology , University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104-6058 , USA

7. Environmental Genomics & System Biology Division , Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720 , USA

8. U.S. Department of Energy Joint Genome Institute , 1 Cyclotron Road, Berkeley, CA 94720

9. School of Natural Sciences , University of California, Merced, Merced, CA , USA

Abstract

Abstract Craniosynostosis, defined by premature fusion of one or multiple cranial sutures, is a common congenital defect affecting more than 1/2000 infants and results in restricted brain expansion. Single gene mutations account for 15-20% of cases, largely as part of a syndrome, but the majority are nonsyndromic with complex underlying genetics. We hypothesized that the two noncoding genomic regions identified by a GWAS for craniosynostosis contain distal regulatory elements for the risk genes BMPER and BMP2. To identify such regulatory elements, we surveyed conserved noncoding sequences from both risk loci for enhancer activity in transgenic Danio rerio. We identified enhancers from both regions that direct expression to skeletal tissues, consistent with the endogenous expression of bmper and bmp2. For each locus, we also found a skeletal enhancer that also contains a sequence variant associated with craniosynostosis risk. We examined the activity of each enhancer during craniofacial development and found that the BMPER-associated enhancer is active in the restricted region of cartilage closely associated with frontal bone initiation. The same enhancer is active in mouse skeletal tissues, demonstrating evolutionarily conserved activity. Using enhanced yeast one-hybrid assays, we identified transcription factors that bind each enhancer and observed differential binding between alleles, implicating multiple signaling pathways. Our findings help unveil the genetic mechanism of the two craniosynostosis risk loci. More broadly, our combined in vivo approach is applicable to many complex genetic diseases to build a link between association studies and specific genetic mechanisms.

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

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