ZFIN ID: ZDB-PUB-150206-3
A Single Nucleotide Polymorphism Associated with Isolated Cleft Lip and Palate, Thyroid Cancer and Hypothyroidism Alters the Activity of an Oral Epithelium and Thyroid Enhancer Near FOXE1
Lidral, A.C., Liu, H., Bullard, S.A., Bonde, G., Machida, J., Visel, A., Moreno Uribe, L.M., Li, X., Amendt, B., Cornell, R.A.
Date: 2015
Source: Human molecular genetics   24(14): 3895-907 (Journal)
Registered Authors: Bonde, Greg, Cornell, Robert
Keywords: none
MeSH Terms:
  • Alleles
  • Animals
  • Cell Line
  • Cleft Lip/genetics*
  • Cleft Palate/genetics*
  • Cloning, Molecular
  • Epithelial Cells/cytology
  • Epithelial Cells/metabolism
  • Epithelium/metabolism
  • Forkhead Transcription Factors/genetics*
  • Forkhead Transcription Factors/metabolism
  • Gene Expression Regulation, Developmental
  • Genetic Loci
  • Green Fluorescent Proteins/genetics
  • Green Fluorescent Proteins/metabolism
  • Humans
  • Hypothyroidism/genetics*
  • Mice
  • Mice, Transgenic
  • Palate/metabolism
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic
  • Thyroid Gland/cytology
  • Thyroid Gland/metabolism
  • Thyroid Neoplasms/genetics*
  • Zebrafish/embryology
  • Zebrafish/genetics
PubMed: 25652407 Full text @ Hum. Mol. Genet.
FIGURES
ABSTRACT
Three common diseases, isolated cleft lip and cleft palate (CLP), hypothyroidism and thyroid cancer all map to the FOXE1 locus, but causative variants have yet to be identified. In patients with CLP the frequency of coding mutations in FOXE1 fails to account for the risk attributable to this locus, suggesting that the common risk alleles reside in nearby regulatory elements. Using a combination of zebrafish and mouse transgenesis, we screened 15 conserved non-coding sequences for enhancer activity, identifying three that regulate expression in a tissue specific pattern consistent with endogenous foxe1 expression. These three, located -82.4 kb, -67.7 kb and +22.6 kb from the FOXE1 start codon, are all active in the oral epithelium or branchial arches. The -67.7 kb and +22.6 kb elements are also active in the developing heart, and the -67.7 kb element uniquely directs expression in the developing thyroid. Within the -67.7 kb element is the SNP rs7850258 that is associated with all three diseases. Quantitative reporter assays in oral epithelial and thyroid cell lines show that the rs7850258 allele (G) associated with CLP and hypothyroidism has significantly greater enhancer activity than the allele associated with thyroid cancer (A). Moreover, consistent with predicted transcription factor binding differences, the -67.7 kb element containing rs7850258 allele G is significantly more responsive to both MYC and ARNT than allele A. By demonstrating that this common non-coding variant alters FOXE1 expression, we have identified at least in part the functional basis for the genetic risk of these seemingly disparate disorders.
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