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RNAseq E16.5 mouse skin Irf6 KO vs WT

ABSTRACT: The integrity of the mammalian epidermis is essential for organism survival, and it depends on a balance of proliferation and differentiation in the resident stem cell population. The kinase Ripk4 and the transcription factor Irf6 are mutated in severe developmental syndromes in humans, and mice lacking these genes display epidermal hyperproliferation and soft tissue fusions, resulting in neonatal lethality. However, the mechanism by which these genes control epidermal differentiation in vivo is unknown. By generating various mouse knock-out and knock-in strains we demonstrate that in vivo the role of Ripk4 in development is dependent on its kinase activity, Ripk4 and Irf6 function cell autonomously in the epidermis,Ripk4 and Irf6 lie on a linear pathway and phosphorylation of Irf6 on Serine413 and Serine424 is essential to prime it for activation. This priming then allows Ripk4 to phosphorylate Irf6 on Serine90, which ensures Irf6 activation. We then use RNA-seq, ChIP-seq and ATAC-seq analysis to define the global transcriptional targets of Irf6 in epidermal differentiation. Collectively, our results explain how Ripk4 activates Irf6, and how this pathway ensures epidermal differentiation and a functional barrier. This is crucial for understanding the etiology of developmental syndromes that are characterized by orofacial, skin and genital abnormalities.

ORGANISM(S): Mus musculus

PROVIDER: GSE124048 | GEO | 2019/08/29

REPOSITORIES: GEO

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RNAseq E15.5 mouse skin WT, Irf6 KO, Ripk4 KD, and Irf6 S413A.S424A knockin

Project description:The integrity of the mammalian epidermis is essential for organism survival, and it depends on a balance of proliferation and differentiation in the resident stem cell population. The kinase Ripk4 and the transcription factor Irf6 are mutated in severe developmental syndromes in humans, and mice lacking these genes display epidermal hyperproliferation and soft tissue fusions, resulting in neonatal lethality. However, the mechanism by which these genes control epidermal differentiation in vivo is unknown. By generating various mouse knock-out and knock-in strains we demonstrate that in vivo the role of Ripk4 in development is dependent on its kinase activity, Ripk4 and Irf6 function cell autonomously in the epidermis,Ripk4 and Irf6 lie on a linear pathway and phosphorylation of Irf6 on Serine413 and Serine424 is essential to prime it for activation. This priming then allows Ripk4 to phosphorylate Irf6 on Serine90, which ensures Irf6 activation. We then use RNA-seq, ChIP-seq and ATAC-seq analysis to define the global transcriptional targets of Irf6 in epidermal differentiation. Collectively, our results explain how Ripk4 activates Irf6, and how this pathway ensures epidermal differentiation and a functional barrier. This is crucial for understanding the etiology of developmental syndromes that are characterized by orofacial, skin and genital abnormalities.

2019-08-29 | GSE124047 | GEO

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Ripk4-Irf6 signaling axis ensures differentiation and barrier function

Project description:Ripk4-Irf6 signaling axis ensures differentiation and barrier function

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Transcription profiling of skin from interferon regulatory factor 6 (Irf6) knockout mice and wild type mice to study the role for Irf6 in epidermal development.

Project description:Transcription factor paralogs may share a common role (e.g. Hox) in staged or overlapping expression in specific tissues. In other examples, members have distinct roles in a range of embryologic, differentiation or response pathways (e.g. Tbx, Pax). For the Interferon Regulatory Factor (IRF) family of transcription factors, mice deficient in Irf1, Irf2, Irf3, Irf4, Irf5, Irf7, Irf8 or Irf9, have defects in the immune response but display no embryologic abnormalities. Mice deficient for Irf6 have not been reported, but in humans, mutations in IRF6 cause two Mendelian orofacial clefting syndrome, and genetic variation in IRF6 confers risk for isolated cleft lip and palate. Mice deficient for Irf6 have abnormal skin, limb and craniofacial development. Histological and gene expression analyses indicate that the primary defect is in keratinocyte differentiation and proliferation. This study describes a novel role for an IRF family member in epidermal development. Experiment Overall Design: Skin from E17.5 mice was removed and flash frozen for RNA extraction and hybridization on Affymetrix microarrays.

2007-11-13 | E-GEOD-5800 | biostudies-arrayexpress

Expression data from mouse IRF6 null and wt skin

2006-10-01 | GSE5800 | GEO

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Project description:We report transcriptional profiles of 4hpf zebrafish embryos from either wild-type or a CRISPR-targeted irf6 loss-of-function mutant. Irf6 is a transcription factor implicated in syndromic and nonsyndromic forms of cleft palate. To define critical genes involved in palate development, we harvested RNA from irf6-/- embryos before an embryonic lethal stage in zebrafish and carried out RNA-sequencing and subsequent analysis. We identify top differentially expressed genes that include genes involved in periderm development, genes expressed in developmental processes (such as Fgfs and Wnt-pathway genes), and genes involved in orofacial clefting. We identify a crucial gene esrp1 that we chose for further validation and downstream analysis.

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RNAseq E15.5 mouse skin WT, Irf6 KO, Ripk4 KD, and Irf6 S413A.S424A knockin

Project description:RNAseq E15.5 mouse skin WT, Irf6 KO, Ripk4 KD, and Irf6 S413A.S424A knockin

| PRJNA510610 | ENA

Interferon Regulatory Factor 6 (IRF6) knockout in human keratinocytes disrupts epithelial homeostasis

Project description:The transcription factor Interferon Regulatory Factor 6 (IRF6) is crucially involved in craniofacial development and regulates the proliferation/differentiation balance in keratinocytes. Pathological IRF6 variants have been found in Van der Woude syndrome (VWS), the most common syndromic form of cleft lip / palate (CLP) as well as in non-syndromic CLP cases. Besides its prominent function in regulating keratinocyte differentiation, recent data revealed that IRF6 is also involved in wound healing and migration. Since a significant fraction of CLP patients undergoing corrective cleft surgery experience wound healing complications, IRF6 represents an interesting candidate gene linking the two processes. However, Irf6 function has been mainly studied in mice and knowledge on IRF6 in human cells remains sparse. Here, we aimed to elucidate the role of IRF6 in human postnatal skin- and oral mucosa-derived keratinocytes by its ablation using CRISPR/Cas9. We complement this approach by applying proteomics and identify that lack of IRF6 disrupts human epithelial homeostasis by altering cell colony morphology, migration pattern, and the differentiation potential of keratinocytes.

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RACK1 prevents premature differentiation of epidermal progenitors by inhibiting IRF6 expression

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2021-11-10 | GSE181265 | GEO

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