Interfollicular epidermal differentiation is gradualistic rather than stepwise with GRHL3 controlling progression from stem to transition cell states
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PROVIDER: PRJNA646723 | ENA |
REPOSITORIES: ENA
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Project description:Although interfollicular epidermal (IFE) differentiation is thought to be stepwise as reflected in sharp boundaries between the basal, spinous, granular and cornified layers, this prediction has not been studied at a single cell resolution. We used single cell RNA-seq to show that IFE differentiation is best described as a single step gradualistic process with a large number of transition cells between the basal and spinous layer. RNA-velocity analysis identifies a commitment point that separates the plastic basal and transition cell state from the unidirectionally differentiating cells. We also show that GRHL3, best known for promoting IFE terminal differentiation, has a major function in suppressing epidermal stem cell expansion and the emergence of an abnormal stem cell state by suppressing Wnt signaling in stem cells.
2020-09-01 | GSE154579 | GEO
Project description:Epidermal barrier repair mechanisms activated in psoriasis lesions are likely involved in limiting the severity of this disease. We show that loss of grainyhead-like 3 (Grhl3), a pro-terminal differentiation factor in the epidermis, is sufficient to trigger greater sensitivity to and delayed resolution of epidermal lesions resulting from either physical or immune mediated barrier injury. After stimulation of Toll like receptors, the loss of Grhl3 resulted in increased epidermal damage with a striking increase in basal cell proliferation, hyperplasia of partially differentiated suprabasal layers, and a transcriptional profile highlighted by the overexpression of epidermal wound response and alarmin genes. This study reveals an important role for the epidermis in the initiation and recovery from immune-mediated lesions, and indicated that the epidermal regulator Grhl3 acts to both suppress disease initiation and resolve existing lesions. This work suggests that treatments focused on improving barrier function could be used preventatively and therapeutically in psoriasis. Whole skin was collected from E16.5 mouse backskins for Grhl3 ChIP. Adult epidermis for depilation and imiquimod experiments was seperated from dermis using dispase prior to Grhl3 ChIP.
2014-09-01 | E-GEOD-52648 | biostudies-arrayexpress
Project description:The skin epidermis is a highly compartmentalised tissue consisting of a cornifying epithelium called the interfollicular epidermis (IFE) and associated hair follicles (HFs). Several stem cell populations have been described that mark specific sub compartments in the skin but none of them is IFE-specific. Here we identify Troy as a marker of IFE and HF infundibulum basal layer cells in embryonic and adult human and mouse epidermis. Genetic lineage-tracing experiments demonstrate that Troy-expressing basal cells contribute to long-term renewal of all layers of the cornifying epithelium. Single-cell transcriptomics and organoid assays of Troy-expressing cells as well as their progeny confirmed stem cell identity as well as the ability to generate differentiating daughter cells. In conclusion, we define Troy as a marker of epidermal basal cells that govern interfollicular epidermal renewal and cornification.
2021-08-05 | GSE165379 | GEO
Project description:The interfollicular epidermis (IFE) forms a water-tight barrier that is often disrupted in inflammatory skin diseases. During homeostasis, the IFE is replenished by stem cells in the basal layer that differentiate as they migrate toward the skin surface. Conventionally, IFE differentiation is thought to be stepwise as reflected in sharp boundaries between its basal, spinous, granular and cornified layers. The transcription factor GRHL3 regulates IFE differentiation by transcriptionally activating terminal differentiation genes. Here we use single cell RNA-seq to show that murine IFE differentiation is best described as a single step gradualistic process with a large number of transition cells between the basal and spinous layer. RNA-velocity analysis identifies a commitment point that separates the plastic basal and transition cell state from unidirectionally differentiating cells. We also show that in addition to promoting IFE terminal differentiation, GRHL3 is essential for suppressing epidermal stem cell expansion and the emergence of an abnormal stem cell state by suppressing Wnt signaling in stem cells.
| S-EPMC7595230 | biostudies-literature
Project description:There are multiple stem cells in adult mammalian epidermis, but the mechanisms controlling lineage specification are poorly understood. To identify gene expression signatures of the three major epidermal differentiation compartments we micro-dissected individual SG, IFE and HF from adult epidermis. The RNA was isolated from age and sex matched wild-type mice and performed transcriptome analysis with Affymetrix Exon microarrays We micro-dissected individual interfollicular epidermis (IFE), hair follicle (HF) and sebaceous gland (SG) from adult tail epidermis. The RNA was isolated from age and sex matched wild-type mice. Three biological replicates for each epidermal differentiation compartment were analyzed.
2017-05-16 | E-GEOD-62604 | biostudies-arrayexpress
Project description:Troy/Tnfrsf19 marks epidermal cells that govern interfollicular epidermal renewal and cornification
| PRJNA694196 | ENA
Project description:Epidermal barrier repair mechanisms activated in psoriasis lesions are likely involved in limiting the severity of this disease. We show that loss of grainyhead-like 3 (Grhl3), a pro-terminal differentiation factor in the epidermis, is sufficient to trigger greater sensitivity to and delayed resolution of epidermal lesions resulting from either physical or immune mediated barrier injury. After stimulation of Toll like receptors, the loss of Grhl3 resulted in increased epidermal damage with a striking increase in basal cell proliferation, hyperplasia of partially differentiated suprabasal layers, and a transcriptional profile highlighted by the overexpression of epidermal wound response and alarmin genes. This study reveals an important role for the epidermis in the initiation and recovery from immune-mediated lesions, and indicated that the epidermal regulator Grhl3 acts to both suppress disease initiation and resolve existing lesions. This work suggests that treatments focused on improving barrier function could be used preventatively and therapeutically in psoriasis.
2014-09-01 | GSE52648 | GEO
Project description:The renewing human epidermis constantly senses and adapts to a wide range of mechanical cues that are ubiquitous throughout life. The mechanisms of how mechanical forces are responded by interfollicular epidermal stem cells (IFESCs) and are transmitted directly into nucleus to modify gene expression was discovered to be mediated by transcriptional coactivators YAP. Interestingly, YAP, a critical modulator in controlling organ size by regulating both cell proliferation and apoptosis, was also found to induce self-renewal or amplification of epidermal progenitor/stem cells, and balance epidermal growth and differentiation. Because growth regulation imposed by different stimuli is achieved through distinct YAP target genes even in a single cell type. This study used chromatin immunoprecipitation (ChIP) coupled with human promoter tiling microarray analysis (ChIP-on-chip) to profile YAP at promoters genome-wide. The goal of the study was to identify the target genes occupied by YAP in IFESCs under the mechanical stretch condition.
2018-07-24 | GSE71314 | GEO
Project description:While the genomic mechanisms underlying progressive, irreversible cell lineage commitments are well-studied, we know little about the chromatin changes during transient cell states such as cell migration. Interestingly, a large number of SEs in NHEK-D and NHEK-M overlap genes encoding transcription factors with important roles in promotion of epidermal differentiation, including GRHL3, TP63, RUNX1, NOTCH3 and FOS. To test the role of these SE-associated transcription factors in a systematic manner, and to place GRHL3 in the context of other keratinocyte differentiation regulators, we used siRNAs to individually knock down GRHL3 and 50 other transcriptional regulators in NHEK-D. These transcriptional regulators were selected based on expression changes during human keratinocyte differentiation. Many have been previously implicated in epidermal differentiation in mice and humans; the genes encoding 22 of them are associated with SEs. To assess the effect of the knockdowns on keratinocyte differentiation, we monitored the expression of approximately 14,000 genes with custom-made Agilent microarrays. Among the 14,000 genes whose expression we monitored were all genes expressed in human keratinocytes and all transcriptional regulators. This 51 x 14,000 gene expression matrix provided a rich dataset to explore gene regulatory networks in epidermal differentiation.
2017-04-12 | GSE86193 | GEO
Project description:The process of differentiation is tightly controlled, and such complex coordination of gene expression requires many layers of regulation. One such mechanism of regulation occurs through distal genomic regions called enhancers, which are believed to act as concentrating sites for transcription factors, like GRHL3, and other regulators, forming loops to contact promoters and enhance transcription. Active enhancers have been shown to have high levels of H3K4me1 and H3K27ac modified nucleosomes, with low levels of H3K4me3, while poised developmental enhancers have been shown to have H3K27me3 in place of H3K27ac. Additionally, in each cell type, a select few enhancers have been found to be unusually long (more than 12.5kb) and show high intensity of transcription factor binding and chromatin enhancer signature marks. These regions, termed super enhancers, are frequently tissue-specific and are thought to regulate the unique gene expression programs in each tissue. ChIP-Seq analysis revealed GRHL3 binding to be strongly enriched within enhancers and super enhancers in differentiating keratinocytes, however the effect of GRHL3 binding on enhancer and super enhancer activity and function is not known.
2017-04-12 | GSE76691 | GEO