ZFIN ID: ZDB-PUB-151223-2
Irf6 directly regulates Klf17 in zebrafish periderm and Klf4 in murine oral epithelium, and dominant-negative KLF4 variants are present in patients with cleft lip and palate
Liu, H., Leslie, E.J., Jia, Z., Smith, T., Eshete, M., Butali, A., Dunnwald, M., Murray, J., Cornell, R.A.
Date: 2016
Source: Human molecular genetics   25(4): 766-76 (Journal)
Registered Authors: Cornell, Robert
Keywords: none
MeSH Terms:
  • Animals
  • Case-Control Studies
  • Cleft Lip/genetics*
  • Cleft Lip/metabolism
  • Cleft Palate/genetics*
  • Cleft Palate/metabolism
  • Female
  • Gene Expression Regulation, Developmental
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Interferon Regulatory Factors/genetics
  • Interferon Regulatory Factors/metabolism*
  • Kruppel-Like Transcription Factors/genetics*
  • Kruppel-Like Transcription Factors/metabolism*
  • Male
  • Mice
  • Mutation
  • Transcription Factors/genetics
  • Transcription Factors/metabolism
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 26692521 Full text @ Hum. Mol. Genet.
Non-syndromic (NS) cleft lip with or without cleft palate (CL/P) is a common disorder with a strong genetic underpinning. Genome wide association studies have detected common variants associated with this disorder, but a large portion of the genetic risk for NSCL/P is conferred by unidentified rare sequence variants. Mutations in IRF6 (Interferon Regulatory Factor 6) and GRHL3 (Grainyhead like 3) cause Van der Woude syndrome, which includes CL/P. Both genes encode members of a regulatory network governing periderm differentiation in model organisms. Here we report that Kr├╝ppel-like factor 17 (Klf17), like Grhl3, acts downstream of Irf6 in this network in zebrafish periderm. Although Klf17 expression is absent from mammalian oral epithelium, a close homolog, Klf4, is expressed in this tissue and is required for the differentiation of epidermis. Chromosome configuration capture and reporter assays indicated that IRF6 directly regulates an oral-epithelium enhancer of KLF4. To test whether rare missense variants of KLF4 contribute risk for NSCL/P, we sequenced KLF4 in approximately 1000 NSCL/P cases and 300 controls. By one statistical test, missense variants of KLF4 as a group were enriched in cases versus controls. Moreover, two patient-derived KLF4 variants disrupted periderm differentiation upon forced expression in zebrafish embryos, suggesting they have dominant negative effect. These results indicate rare NSCL/P risk variants can be found in members of the gene regulatory network governing periderm differentiation.