Ripk4-Irf6 signaling axis ensures differentiation and barrier function
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ABSTRACT:
PROVIDER: PRJNA510640 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8349440.fastq.gz | Fastqsanger.gz | |||
| SRR8349450.fastq.gz | Fastqsanger.gz | |||
| SRR8349460.fastq.gz | Fastqsanger.gz | |||
| SRR8349441.fastq.gz | Fastqsanger.gz | |||
| SRR8349451.fastq.gz | Fastqsanger.gz |
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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
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 | GSE127341 | GEO
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 | GSE127338 | GEO
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 | GSE124048 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-08-29 | GSE124067 | GEO
Project description:RNAseq E15.5 mouse skin WT, Irf6 KO, Ripk4 KD, and Irf6 S413A.S424A knockin
| PRJNA510610 | ENA
Project description:Receptor-interacting serine/threonine protein kinase 4 (RIPK4) and its kinase substrate the transcription factor interferon regulatory factor 6 (IRF6) play critical roles in the development and maintenance of the epidermis. In addition, ourselves and others have previously shown that RIPK4 is a NOTCH target gene that suppresses the development of cutaneous and head and neck squamous cell carcinomas (HNSCCs). In this study, we used autochthonous mouse models, where the expression of Pik3caH1047R oncogene predisposes the skin and oral cavity to tumor development, and show that not only loss of Ripk4, but also loss of its kinase substrate Irf6, triggers rapid SCC development. In vivo rescue experiments using Ripk4 or a kinase-dead Ripk4 mutant showed that the tumor suppressive function of Ripk4 is dependent on its kinase activity. To elucidate critical mediators of this tumor suppressive pathway, we performed transcriptional profiling of Ripk4-deficient epidermal cells followed by multiplexed in vivo CRISPR screening to identify genes with tumor suppressive capabilities. We show that Elovl4 is a critical Notch-Ripk4-Irf6 downstream target gene, and that Elovl4 loss itself triggers SCC development. Importantly, overexpression of Elovl4 suppressed tumor growth of Ripk4-deficient keratinocytes. Altogether, our work identifies a potent Notch1-Ripk4-Irf6-Elovl4 tumor suppressor axis.
| S-EPMC9913669 | biostudies-literature
Project description:One of the most critical axes for cell fate determination is how cells respond to excessive reactive oxygen species (ROS)-oxidative stress. Extensive lipid peroxidation commits cells to death via a distinct cell death paradigm termed ferroptosis. However, the molecular mechanism regulating cellular fates to distinct ROS remains incompletely understood. Through siRNA against human receptor-interacting protein kinases (RIPK) family members, we discovered that RIPK4 is crucial for oxidative stress and ferroptotic death. Upon ROS induction, RIPK4 is rapidly activated and the kinase activity of RIPK4 is indispensable to induce cell death. Specific ablation of RIPK4 in kidney proximal tubules protects mice from acute kidney injury induced by cisplatin and renal ischemia/reperfusion. RNA sequencing revealed the dramatically decreased expression of acyl-CoA synthetase medium-chain (ACSM) family members induced by cisplatin treatment which is compromised in RIPK4 deficient mice. Among these ACSM family members, suppression of ACSM1 strongly augments oxidative stress and ferroptotic cell death with induced expression of ACSL4, an important component for ferroptosis execution. Our lipidome analysis revealed that over-expression of ACSM1 leads to the accumulation of monounsaturated fatty acids (MUFAs), attenuation of polyunsaturated fatty acids (PUFAs) production, and thereby cellular resistance to ferroptosis. Hence, knock-down ACSM1 re-sensitizes RIPK4 KO cells to oxidative stress and ferroptotic death. In conclusion, RIPK4 is a key player involved in oxidative stress and ferroptotic death, which is potentially important for a broad spectrum of human pathologies. The link between RIPK4-ASCM1 axis to PUFAs and ferroptosis reveals a novel mechanism to oxidative stress induced necrosis and ferroptosis.
2024-09-04 | GSE276038 | GEO
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.
2022-02-17 | PXD027669 | Pride
Project description:RIPK4 but not the related kinases RIPK1, RIPK2, and RIPK3 caused similar transcriptional changes to Wnt3a. PA1 cells were transfected by 8ug RIPK1, RIPK2, RIPK3, or RIPK4 for 48h, RNA were extracted and sequenced.
2013-02-04 | E-GEOD-43362 | biostudies-arrayexpress