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

Huan Liu; Elizabeth J Leslie; Zhonglin Jia; Tiffany Smith; Mekonen Eshete; Azeez Butali; Martine Dunnwald; Jeffrey Murray; Robert A Cornell

doi:10.1093/hmg/ddv614

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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

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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

Huan Liu, Elizabeth J Leslie, Zhonglin Jia, Tiffany Smith, Mekonen Eshete, Azeez Butali, Martine Dunnwald, Jeffrey Murray and Robert A Cornell

Human molecular genetics, Vol.25(4), pp.766-776

02/15/2016

DOI: 10.1093/hmg/ddv614

PMCID: PMC4743694

PMID: 26692521

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Abstract

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 Krüppel-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 homologue, 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 that they have dominant-negative effect. These results indicate that rare NSCL/P risk variants can be found in members of the gene regulatory network governing periderm differentiation.

Genetic Predisposition to Disease

Genome-Wide Association Study

Zebrafish Proteins - metabolism

Humans

Interferon Regulatory Factors - metabolism

Interferon Regulatory Factors - genetics

Male

Zebrafish

Cleft Palate - genetics

Transcription Factors - genetics

Cleft Lip - metabolism

Case-Control Studies

Transcription Factors - metabolism

Cleft Lip - genetics

Animals

Gene Expression Regulation, Developmental

Kruppel-Like Transcription Factors - metabolism

Female

Cleft Palate - metabolism

Mice

Mutation

Zebrafish Proteins - genetics

Kruppel-Like Transcription Factors - genetics

Details

Title: Subtitle: 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
Creators: Huan Liu - Department of Anatomy and Cell Biology, College of Medicine, State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
Elizabeth J Leslie - Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA
Zhonglin Jia - Department of Pediatrics, College of Medicine and, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China and
Tiffany Smith - Department of Anatomy and Cell Biology, College of Medicine
Mekonen Eshete - Department of Burns and Plastic Surgery, Addis Ababa University, Addis Ababa, Ethiopia
Azeez Butali - Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa, Iowa City, IA, USA
Martine Dunnwald - Department of Pediatrics, College of Medicine and
Jeffrey Murray - Department of Pediatrics, College of Medicine and
Robert A Cornell - Department of Anatomy and Cell Biology, College of Medicine, robert-cornell@uiowa.edu
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.25(4), pp.766-776
DOI: 10.1093/hmg/ddv614
PMID: 26692521
PMCID: PMC4743694
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: England
Grant note: R01 DE023575 / NIDCR NIH HHS K99-DE025060 / NIDCR NIH HHS R01 AR067739 / NIAMS NIH HHS R00 DE022378 / NIDCR NIH HHS HD073107 / NICHD NIH HHS K99/R00DE022378 / NIDCR NIH HHS DE08559 / NIDCR NIH HHS K99 DE025060 / NIDCR NIH HHS
Language: English
Date published: 02/15/2016
Academic Unit: Oral Pathology, Radiology and Medicine; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9984025441502771

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