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Glucose controls protein-protein interactions and tissue differentiation [RNA-Seq]

ABSTRACT: Abstract: Glucose serves as a universal energy currency in living organisms, however, its potential non-energetic biomolecular functions are less well defined. Glucose was among the most increased analytes among >14,000 assessed across epidermal differentiation, an elevation verified in tissue engineered with fluorescent glucose sensors and also observed in differentiating cells from other tissues. Free glucose accumulation, but not its increased metabolism, was essential for epidermal differentiation and required GLUT1, GLUT3, and SLC5A1 transporters. Glucose affinity chromatography and azido-glucose click chemistry revealed direct glucose binding to a variety of regulatory proteins, including the IRF6 transcription factor (TF), whose epidermal knockout confirmed its requirement in glucose-dependent differentiation. Glucose binding mediated IRF6 dimerization, DNA affinity, and genomic targeting. The IRF6R84C mutant found in poorly differentiated cancers was unable to bind glucose. These data demonstrate a non-energetic role for glucose in modulating protein multimerization to control genome dynamics. Purpose: To assess the global transcriptional program in epidermal organoids where glucose has been modulated and to assess the transcriptome in the context of IRF6 loss.

ORGANISM(S): Homo sapiens

PROVIDER: GSE197202 | GEO | 2025/02/21

REPOSITORIES: GEO

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Glucose controls protein-protein interactions and tissue differentiation [ChIP-Seq]

Project description:Abstract: Glucose serves as a universal energy currency in living organisms, however, its potential non-energetic biomolecular functions are less well defined. Glucose was among the most increased analytes among >14,000 assessed across epidermal differentiation, an elevation verified in tissue engineered with fluorescent glucose sensors and also observed in differentiating cells from other tissues. Free glucose accumulation, but not its increased metabolism, was essential for epidermal differentiation and required GLUT1, GLUT3, and SLC5A1 transporters. Glucose affinity chromatography and azido-glucose click chemistry revealed direct glucose binding to a variety of regulatory proteins, including the IRF6 transcription factor (TF), whose epidermal knockout confirmed its requirement in glucose-dependent differentiation. Glucose binding mediated IRF6 dimerization, DNA affinity, and genomic targeting. The IRF6R84C mutant found in poorly differentiated cancers was unable to bind glucose. These data demonstrate a non-energetic role for glucose in modulating protein multimerization to control genome dynamics. Purpose: To determine the impact of glucose modulation on IRF6 genomic localization during keratinocyte differentiation

2025-02-21 | GSE197201 | GEO

Glucose controls protein-protein interactions and tissue differentiation [ATAC-Seq]

Project description:Abstract: Glucose serves as a universal energy currency in living organisms, however, its potential non-energetic biomolecular functions are less well defined. Glucose was among the most increased analytes among >14,000 assessed across epidermal differentiation, an elevation verified in tissue engineered with fluorescent glucose sensors and also observed in differentiating cells from other tissues. Free glucose accumulation, but not its increased metabolism, was essential for epidermal differentiation and required GLUT1, GLUT3, and SLC5A1 transporters. Glucose affinity chromatography and azido-glucose click chemistry revealed direct glucose binding to a variety of regulatory proteins, including the IRF6 transcription factor (TF), whose epidermal knockout confirmed its requirement in glucose-dependent differentiation. Glucose binding mediated IRF6 dimerization, DNA affinity, and genomic targeting. The IRF6R84C mutant found in poorly differentiated cancers was unable to bind glucose. These data demonstrate a non-energetic role for glucose in modulating protein multimerization to control genome dynamics. Purpose: To determine the impact of glucose modulation on chromatin accessibility during keratinocyte differentiation and the impact of IRF6 loss on chromatin accessibilty in differentiated keratincoytes

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Irf6 wildtype and knock out ChIP-seq

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.

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RNAseq E16.5 mouse skin Irf6 KO vs WT

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Irf6 wildtype and knock out ATAC-seq

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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.

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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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Interferon Regulatory Factor 6 Determines Epithelial Cell Development and Immunity 2

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