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Nature
10, 2019;574 (7777): 249-253.

The RIPK4-IRF6 signalling axis safeguards epidermal differentiation and barrier function.

Nina Oberbeck, Victoria C Pham, Joshua D Webster, Rohit Reja, Christine S Huang, Yue Zhang, Merone Roose-Girma, Søren Warming, Qingling Li, Andrew Birnberg, Weng Wong, Wendy Sandoval, László G Kőműves, Kebing Yu, Debra L Dugger, Allie Maltzman, Kim Newton, Vishva M Dixit
Author Information
  1. Nina Oberbeck: Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
  2. Victoria C Pham: Department of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, CA, USA.
  3. Joshua D Webster: Department of Pathology, Genentech, South San Francisco, CA, USA.
  4. Rohit Reja: Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA, USA.
  5. Christine S Huang: Department of Protein Chemistry, Genentech, South San Francisco, CA, USA.
  6. Yue Zhang: Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA, USA.
  7. Merone Roose-Girma: Department of Molecular Biology, Genentech, South San Francisco, CA, USA.
  8. Søren Warming: Department of Molecular Biology, Genentech, South San Francisco, CA, USA.
  9. Qingling Li: Department of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, CA, USA.
  10. Andrew Birnberg: Department of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, CA, USA.
  11. Weng Wong: Department of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, CA, USA.
  12. Wendy Sandoval: Department of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, CA, USA.
  13. László G Kőműves: Department of Pathology, Genentech, South San Francisco, CA, USA.
  14. Kebing Yu: Department of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, CA, USA.
  15. Debra L Dugger: Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
  16. Allie Maltzman: Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
  17. Kim Newton: Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
  18. Vishva M Dixit: Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA. dixit@gene.com.
PMID: 31578523 DOI: 10.1038/s41586-019-1615-3

Abstract

The integrity of the mammalian epidermis depends on a balance of proliferation and differentiation in the resident population of stem cells. 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 that result in neonatal lethality. Our understanding of how these genes control epidermal differentiation is incomplete. Here we show that the role of RIPK4 in mouse development requires its kinase activity; that RIPK4 and IRF6 expressed in the epidermis regulate the same biological processes; and that the phosphorylation of IRF6 at Ser413 and Ser424 primes IRF6 for activation. Using RNA sequencing (RNA-seq), histone chromatin immunoprecipitation followed by sequencing (ChIP-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) of skin in wild-type and IRF6-deficient mouse embryos, we define the transcriptional programs that are regulated by IRF6 during epidermal differentiation. IRF6 was enriched at bivalent promoters, and IRF6 deficiency caused defective expression of genes that are involved in the metabolism of lipids and the formation of tight junctions. Accordingly, the lipid composition of the stratum corneum of Irf6 skin was abnormal, culminating in a severe defect in the function of the epidermal barrier. Collectively, our results explain how RIPK4 and IRF6 function to ensure the integrity of the epidermis and provide mechanistic insights into why developmental syndromes that are characterized by orofacial, skin and genital abnormalities result when this axis goes awry.

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MeSH Term

Abnormalities, Multiple
Animals
Cell Differentiation
Cleft Lip
Cleft Palate
Cysts
Embryo, Mammalian
Epidermal Cells
Epidermis
Eye Abnormalities
Female
Fingers
Gene Expression Regulation
Interferon Regulatory Factors
Knee
Knee Joint
Lip
Lipid Metabolism
Lower Extremity Deformities, Congenital
Male
Mice
Mice, Inbred C57BL
Phosphorylation
Phosphoserine
Protein Serine-Threonine Kinases
Signal Transduction
Syndactyly
Urogenital Abnormalities

Chemicals

IRF6 protein, mouse
Interferon Regulatory Factors
Phosphoserine
Protein Serine-Threonine Kinases
Ripk4 protein, mouse
Journal Article
Article has an altmetric score of 32

Word Cloud

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