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 and Vishva M. Dixit ()
Additional contact information
Nina Oberbeck: Genentech
Victoria C. Pham: Proteomics and Lipidomics, Genentech
Joshua D. Webster: Genentech
Rohit Reja: Genentech
Christine S. Huang: Genentech
Yue Zhang: Genentech
Merone Roose-Girma: Genentech
Søren Warming: Genentech
Qingling Li: Proteomics and Lipidomics, Genentech
Andrew Birnberg: Proteomics and Lipidomics, Genentech
Weng Wong: Proteomics and Lipidomics, Genentech
Wendy Sandoval: Proteomics and Lipidomics, Genentech
László G. Kőműves: Genentech
Kebing Yu: Proteomics and Lipidomics, Genentech
Debra L. Dugger: Genentech
Allie Maltzman: Genentech
Kim Newton: Genentech
Vishva M. Dixit: Genentech

Nature, 2019, vol. 574, issue 7777, 249-253

Abstract: Abstract The integrity of the mammalian epidermis depends on a balance of proliferation and differentiation in the resident population of stem cells1. 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 lethality2–5. 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.

Date: 2019
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DOI: 10.1038/s41586-019-1615-3

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