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Metabolic drivers of human keratinocyte differentiation revealed by integrated metabolome and transcriptome analysis

ABSTRACT: Epidermal function is maintained through a continuous process called epidermal homeostasis, in which keratinocytes gradually differentiate from proliferating stem cells to dead corneocytes that shed off the skin. We investigated the metabolic rewiring that occur during keratinocyte differentiation. We analyzed endometabolome, exometabolome and transcriptome during differentiating in vitro under high calcium conditions. Using network-based computational approaches, we found that proliferating keratinocytes gain energy through branched-chain amino acid-fueled TCA cycle that is shut down during differentiation. Upon differentiation, metabolism is repurposed to serve two main purposes. First, to form the epidermal barrier. Specifically, glucose and nucleotides are utilized for the formation of the lipid-enriched hydrophobic extracellular matrix, the transformation from keratinocytes to corneocytes and their cross-linking. Second, we found active regulation of metabolites with signaling functions during differentiation including hydrocortisone, sphingosines, and exonucleotides. Functional relevance of these findings was tested experimentally by 14 metabolic perturbations that were inferred by our analysis, and effectively affected keratinocytes differentiation and proliferation. Overall, this work provides an integrated and mechanistic analysis of the metabolic underpinnings that sustain epidermal function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE136375 | GEO | 2020/01/01

REPOSITORIES: GEO

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Project description:Targets of Retinoic Acid (RA) and 3,4-didehydroretinoic acid (ddRA) were identified in primary human epidermal keratinocytes grown in the presence of atRA or ddRA for 4 and 24 hours. Retinoids (natural forms and synthetic derivatives of vitamin A) are used as therapeutic agents for numerous skin diseases such as keratinization disorders (e.g. ichthyoses) and psoriasis. Two endogenous ligands for retinoic acid receptors exist, retinoic acid (atRA) and 3,4-didehydroretinoic acid (ddRA). In primary human epidermal keratinocytes many transcriptional targets for atRA are known, whereas the targets for ddRA are unknown. In an attempt to determine the targets, we compared the effect of atRA and ddRA on transcriptional profiles in undifferentiated and differentiating human primary keratinocytes. First, as expected, many genes were induced or suppressed in response to keratinocyte differentiation. Furthermore, the two retinoids affected substantially more genes in differentiated keratinocytes (more than 350) than in proliferating keratinocytes (20). In differentiating keratinocytes markers of cornification were suppressed suggesting a de-differentiating effect by the two retinoids. When comparing the expression profile of atRA to that of ddRA, no differently regulated genes were found. The array analysis also found that a minor number of miRNAs and a large number of non-coding transcripts were changed during differentiation and in response to the two retinoids. Furthermore, the expression of all, except one, genes known to cause autosomal recessive congenital ichthyosis (ARCI) were found to be induced by differentiation. These results comprehensively document that atRA and ddRA exert similar transcriptional changes in keratinocytes and also add new insights into the molecular mechanism influenced by retinoids in the epidermis. Furthermore, it suggests which ARCI patients could benefit from therapy with retinoids. Proliferating and differentiated keratinocytes were harvested after 4 and 24 hours after treatment with atRA, ddRA and vehicle for RNA extraction and hybridization on Affymetrix microarrays. Triplicate samples were generated for each time point and each treatment.

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Metabolic drivers of human keratinocyte differentiation revealed by integrated metabolome and transcriptome analysis

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