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Interferon Regulatory Factor 6 Controls Proliferation of Keratinocytes From Children With Van der Woude Syndrome.

ABSTRACT: Interferon Regulatory Factor 6 (IRF6) is critical for craniofacial development, epidermal differentiation, and tissue repair. IRF6 mutations cause Van der Woude Syndrome (VWS) and Popliteal Pterygium Syndrome. Individuals with VWS exhibit craniofacial anomalies, including cleft lip and palate and lip pits. Furthermore, they have an increased risk for wound-healing complications following surgical repair when compared with patients with nonsyndromic cleft lip and palate (NSCLP). However, nothing is known about the skin of these patients. The objective was to characterize the skin of patients with VWS. We hypothesize that IRF6 is required for proper skin homeostasis in humans.Discarded tissue from a hip was collected during surgical alveolar bone graft. Samples from children with VWS harboring IRF6 mutations (n = 2) were compared with samples from children with NSCLP (n = 7). Histology was assessed following hematoxylin and eosin staining. The expressions of Proliferating Cell Nuclear Antigen, IRF6, P63, and Keratin 10 were determined by immunofluorescence. Keratinocytes were isolated and their proliferation potential was assessed by colony-forming efficiency assay.Hip skin from children with VWS showed a thicker epidermis when compared with that from children with NSCLP. Proliferating Cell Nuclear Antigen staining revealed an increase in proliferation in syndromic tissues when compared with controls. However, P63 and Keratin 10 expression were similar between groups. Finally, keratinocytes from VWS showed increased long-term proliferation when compared with NSCLP.These results support, in vivo and in vitro, a previously described role for IRF6 in epidermal proliferation in humans. They further demonstrate a critical function for IRF6 in cutaneous homeostasis.

SUBMITTER: Hixon K

PROVIDER: S-EPMC5776006 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Interferon Regulatory Factor 6 Controls Proliferation of Keratinocytes From Children With Van der Woude Syndrome.

Hixon Katherine K Rhea Lindsey L Standley Jennifer J Canady Frank J FJ Canady John W JW Dunnwald Martine M

The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 20160426 3

<h4>Objective</h4>Interferon Regulatory Factor 6 (IRF6) is critical for craniofacial development, epidermal differentiation, and tissue repair. IRF6 mutations cause Van der Woude Syndrome (VWS) and Popliteal Pterygium Syndrome. Individuals with VWS exhibit craniofacial anomalies, including cleft lip and palate and lip pits. Furthermore, they have an increased risk for wound-healing complications following surgical repair when compared with patients with nonsyndromic cleft lip and palate (NSCLP). ...[more]

PMID: 27115562

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Project description:IntroductionVan der Woude Syndrome (VWS) is an autosomal dominant disorder responsible for 2% of all syndromic orofacial clefts (OFCs) with IRF6 being the primary causal gene (70%). Cases may present with lip pits and either cleft lip, cleft lip with cleft palate, or cleft palate, with marked phenotypic discordance even among individuals carrying the same mutation. This suggests that genetic or epigenetic modifiers may play additional roles in the syndrome's etiology and variability in expression. We report the first DNA methylation profiling of 2 pairs of monozygotic twins with VWS. Our goal is to explore epigenetic contributions to VWS etiology and variable phenotypic expressivity by comparing DNAm profiles in both twin pairs. While the mutations that cause VWS in these twins are known, the additional mechanism behind their phenotypic risk and variability in expression remains unclear.MethodsWe generated whole genome DNAm data for both twin pairs. Differentially methylated positions (DMPs) were selected based on: (1) a coefficient of variation in DNAm levels in unaffected individuals < 20%, and (2) intra-twin pair absolute difference in DNAm levels >5% (delta beta > | 0.05|). We then divided the DMPs in two subgroups for each twin pair for further analysis: (1) higher methylation levels in twin A (Twin A > Twin B); and (2) higher methylation levels in twin B (Twin B >Twin A).Results and discussionGene ontology analysis revealed a list of enriched genes that showed significant differential DNAm, including clef-associated genes. Among the cleft-associated genes, TP63 was the most significant hit (p=7.82E-12). Both twin pairs presented differential DNAm levels in CpG sites in/near TP63 (Twin 1A > Twin 1B and Twin 2A < Twin 2B). The genes TP63 and IRF6 function in a biological regulatory loop to coordinate epithelial proliferation and differentiation in a process that is critical for palatal fusion. The effects of the causal mutations in IRF6 can be further impacted by epigenetic dysregulation of IRF6 itself, or genes in its pathway. Our data shows evidence that changes in DNAm is a plausible mechanism that can lead to markedly distinct phenotypes, even among individuals carrying the same mutation.

Dataset Information

Interferon Regulatory Factor 6 Controls Proliferation of Keratinocytes From Children With Van der Woude Syndrome.

Publications

Interferon Regulatory Factor 6 Controls Proliferation of Keratinocytes From Children With Van der Woude Syndrome.

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