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

被引：45

作者：

Liu, Huan ^{[1
,4
,5
]}

Leslie, Elizabeth J. ^{[6
]}

Jia, Zhonglin ^{[2
,7
]}

Smith, Tiffany ^{[1
]}

Eshete, Mekonen ^{[8
]}

Butali, Azeez ^{[3
]}

Dunnwald, Martine ^{[2
]}

Murray, Jeffrey ^{[2
]}

Cornell, Robert A. ^{[1
]}

机构：

[1] Univ Iowa, Coll Med, Dept Anat & Cell Biol, Iowa City, IA 52242 USA

[2] Univ Iowa, Coll Med, Dept Pediat, Iowa City, IA 52242 USA

[3] Univ Iowa, Coll Dent, Dept Oral Pathol Radiol & Med, Iowa City, IA 52242 USA

[4] Wuhan Univ, Sch & Hosp Stomatol, Minist Educ, State Key Lab Breeding Base Basic Sci Stomatol Hu, Wuhan 430079, Peoples R China

[5] Wuhan Univ, Sch & Hosp Stomatol, Minist Educ, Key Lab Oral Biomed, Wuhan 430079, Peoples R China

[6] Univ Pittsburgh, Sch Dent Med, Dept Oral Biol, Ctr Craniofacial & Dent Genet, Pittsburgh, PA USA

[7] Sichuan Univ, West China Hosp Stomatol, State Key Lab Oral Dis, Chengdu 610041, Sichuan, Peoples R China

[8] Univ Addis Ababa, Dept Burns & Plast Surg, Addis Ababa, Ethiopia

来源：

HUMAN MOLECULAR GENETICS | 2016年 / 25卷 / 04期

基金：

中国国家自然科学基金;

关键词：

GENOME-WIDE ASSOCIATION; KRUPPEL-LIKE FACTORS; TRANSCRIPTION FACTOR; SUSCEPTIBILITY LOCUS; CAUSE VAN; NETWORK; EXPRESSION; GENETICS; RISK; DIFFERENTIATION;

D O I：

10.1093/hmg/ddv614

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 Kruppel-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,

引用

页码：766 / 776

页数：11