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Single Cell and Open Chromatin Analysis Reveals Molecular Origin of Epidermal Cells of the Skin

ABSTRACT: Skin and its appendages such as hair follicle and sweat gland are formed by Keratin-5 expressing (Krt5+) epidermal cells that are specified from primitive, Keratin-8 expressing (Krt8+) ectodermal progenitors shortly after gastrulation. Here we show that transcription factor ∆Np63 is required for converting Krt8+ ectodermal progenitors to Krt5+ epidermal progenitors and priming the underlying dermal cells to form dermal condensate by activating the Wnt/ß-Catenin pathway. These findings unearth the molecular cascades during the fate specification of epidermal cells, illuminate the essential role of ∆Np63 in initiating the Wnt signaling in the epidermis and programming the underlying dermal cells and provide new possibilities to harness the intrinsic developmental program for generating the skin and its appendages.

ORGANISM(S): Mus musculus

PROVIDER: GSE102086 | GEO | 2018/09/05

REPOSITORIES: GEO

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Single Cell and Open Chromatin Analysis Reveals Molecular Origin of Epidermal Cells of the Skin

Project description:Skin and its appendages such as hair follicle and sweat gland are formed by Keratin-5 expressing (Krt5+) epidermal cells that are specified from primitive, Keratin-8 expressing (Krt8+) ectodermal progenitors shortly after gastrulation. Here we show that transcription factor ∆Np63 is required for converting Krt8+ ectodermal progenitors to Krt5+ epidermal progenitors and priming the underlying dermal cells to form dermal condensate by activating the Wnt/ß-Catenin pathway. These findings unearth the molecular cascades during the fate specification of epidermal cells, illuminate the essential role of ∆Np63 in initiating the Wnt signaling in the epidermis and programming the underlying dermal cells and provide new possibilities to harness the intrinsic developmental program for generating the skin and its appendages.

2018-09-05 | GSE97213 | GEO

Transcriptome profiling of normal and transformed mouse urothelial cells

Project description:Transcriptome analysis of urothelial KRT5-traced and KRT8-traced YFP-sorted cells with and without combinatorial loss of Trp53 and Pten. Bladders from 2-month-old KRT5-CreERT2, Rosa26YFP/LacZ mice, 2-month-old KRT8-CreERT2, Rosa26YFP/LacZ mice, 5-month-old KRT5-CreERT2, p53flox/flox, Ptenflox/flox, Rosa26YFP/+ mice, and 5-month-old KRT8-CreERT2, p53flox/flox, Ptenflox/flox, Rosa26YFP/+ mice were enzymatically dissociated, sorted for YFP by FACS, harvested, resuspended in Trizol and snap frozen for subsequent molecular analysis.

2019-01-01 | GSE110694 | GEO

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Project description:The epidermis and associated appendages ensure a number of critical functions necessary for survival and social interactions. Perturbations of epidermal stem cell homeostasis lead to a variety of skin diseases affecting humans and dogs. Therefore, the establishment of an in vitro system to investigate canine epidermal stem cells, representing a model for human diseases, is essential. Here we report the establishment and characterization of organoids derived from microdissected canine hair follicles (HFs) and interfollicular epidermal (IFE). Gene and protein expression analysis revealed high mRNA and protein levels of keratin 5 and 14, IFE differentiation markers and intercellular molecules (e.g., keratin 10 and desmoglein), indicating a strong basal cell signature as well as differentiation towards mature epidermis. Key markers of HF stem cells were lacking. This suggests that, independently of the tissue of origin, both organoid lines develop into the same cell type (basal IFE-like keratinocytes). Signaling pathways members important for regulation of HF growth and cycling (such as Wnt, Hh, BMP and Notch) were present in both HF and IFE organoids at low levels. Withdrawal of growth factors (Noggin, R-spondin and FGFs) resulted in upregulation of markers such as KRT16, IVL, KRT17 and SOX9, showing the potential of the organoids to develop towards more differentiated tissue. However, for induction of HF signatures or hair growth, addition of different growth factors or dermal papilla co-culture might be required. Taken together, our in vitro culture system can provide the basis to address hair growth and explore epidermal function/regeneration, allowing us to further investigate pathomechanisms of cutaneous disorders in dogs and potentially human patients.

2018-07-02 | GSE104622 | GEO

Regional specific differentiation of integumentary organs: SATB2 is involved in α- and β-keratin gene cluster switching in the chicken

Project description:Animals develop skin regional specificities to best adapt to their environments. Birds are excellent models in which to study the epigenetic mechanisms that facilitate these adaptions. Patients suffering from SATB2 mutations exhibit multiple defects including ectodermal dysplasia-like changes. The preferential expression of SATB2, a chromatin regulator, in feather-forming compared to scale-forming regions, suggests it functions in regional specification of chicken skin appendages by acting on either differentiation or morphogenesis. Retrovirus mediated SATB2 misexpression in developing feathers, beaks, and claws causes epidermal differentiation abnormalities (e.g. knobs, plaques) with few organ morphology alterations. Chicken β-keratins are encoded in 5 sub-clusters (Claw, Feather, Feather-like, Scale, and Keratinocyte) on Chromosome 25 and a large Feather keratin cluster on Chromosome 27. Type I and II α-keratin clusters are located on Chromosomes 27 and 33, respectively. Transcriptome analyses showed these keratins 1) are often tuned up or down collectively as a sub-cluster, and 2) these changes occur in a temporo-spatial specific manner. This cluster-level suppression is also seen in MMPs on Chromosome 1. SATB2 alters gene expression changes of most other transcripts without this cluster-level switching. These results suggest an organizing role of SATB2 in cluster-level gene co-regulation during skin regional specification.

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Comparative spatial transcriptomic and single-cell analyses of human nail units and hair follicles demonstrate transcriptional similarities between the onychodermis and follicular dermal papilla

Project description:The nail unit and hair follicle are both hard keratin-producing organs that share various biological features. In this study, we demonstrated the presence of a nail-specific mesenchymal population called onychofibroblasts within the onychodermis. Onychodermis and follicular dermal papilla (DP) both expressed WNT and bone morphogenetic protein (BMP) signaling molecules. To analyze the function of BMP5 in nail development, we treated cultured human nail matrix keratinocytes (NMKs) with BMP5, which are highly expressed by onychofibroblasts. We observed increased expressions of hard keratin and HOXC13.

2022-07-02 | GSE193269 | GEO

ChIP-seq analysis comparing WT, TAp63-/-, and ΔNp63-/- primary murine keratinocytes

Project description:The p53 family member TP63 encodes two sets of isoforms, TAp63 and ∆Np63 isoforms, which are characterized by different N-termini and have diverse biological functions in epidermal morphogenesis and in cancer. In the skin, where their activities are best characterized, TAp63 prevents premature aging by regulating cellular senescence and genomic stability of stem cells, while ∆Np63 controls terminal differentiation of the basal cells in the epidermis. This functional diversity is surprising given that these isoforms share a high degree of similarity, including an identical DNA binding domain. To understand the mechanisms involved in the transcriptional programs leading to these diverse biological functions, we performed genome-wide analyses using p63-ChIP-seq and RNA-seq of TAp63-/- and ∆Np63-/- compared to wild-type primary mouse epidermal cells. Our data indicate that TAp63 and ∆Np63 recognize significantly different response elements on DNA and can physically and functionally interact with distinct transcription factors for the downstream regulation of their target genes. Our findings unveil previously uncharacterized transcriptomes activated by the p63 isoforms to regulate diverse biological functions in epidermal morphogenesis and homeostasis and cancer.

2023-12-06 | GSE147723 | GEO

Single-Cell RNA-Seq Analysis of long-term transplanted single-cell-derived mouse DASC in host lung

Project description:Distal airway stem cell (DASC) expressing basal cell restrictive transcription factor p63 and keratin-5 (Krt5) has a strong ability of regeneration after lung injury. Such cells are originated from primitive progenitors in distal airways and could expand/migrate to inflamed damaged lung parenchymal region to form ‘KRT5 pods’ once activated by various types of tissue injury. We isolated the mouse DASC and transplanted the GFP-labelled mDASC into the bleomycin-injured mouse lung by intratracheal instillation. Mice were sacrificed at 30 and 90 days post transplantation and their lung tissue were harvest to detect GFP signal by fluorescence stereomicroscope, the region of which was dissect for single cell-RNA-seq (scRNA-seq). We utilized scRNA-seq to trace the fate of transplanted mDASCs at 30 days and 90 days post transplantation, which revealed cell types differentiated from the transplanted DASCs.

2021-03-10 | GSE168573 | GEO

Epigenome analysis of human epidermal and dermal samples with aging and sun exposure

Project description:Genome wide DNA methylation profiling of epidermal and dermal samples obtained from sun-exposed and sun-protected body sites from younger (<35 years old) and older (>60 years old) individuals. The Illumina Infinium 450k Human DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 450,000 CpGs in dermal and epidermal samples. Samples included 10 younger sun protected dermal samples, 10 younger sun exposed dermal samples, 10 older sun protected dermal samples, 10 older sun exposed dermal samples, 9 younger sun protected epidermal samples, 9 younger sun exposed epidermal samples, 10 older sun protected epidermal sample, 10 older sun exposed epidermal samples.

2015-03-23 | GSE51954 | GEO

Beta-catenin stabilization of skin fibroblasts causes fibrotic lesions by preventing adipocyte differentiation of the reticular dermis

Project description:The Wnt/alpha-catenin pathway plays a central role in epidermal homeostasis and regeneration but how it affects fibroblast fate decisions is unknown. Here, we investigated the effect of targeted alpha-catenin stabilization in dermal fibroblasts. Comparative gene expression profiling of Sca1- and Sca1+ neonatal fibroblasts, from upper and lower dermis respectively, confirmed that Sca1+ cells had a pre-adipocyte signature and revealed differential expression of Wnt/alpha‐catenin-associated genes. By targeting all fibroblasts or selectively targeting Dlk1+ lower dermal fibroblasts, we found that -catenin stabilization between E16.5 and P2 resulted in a reduction in the dermal adipocyte layer with a corresponding increase in dermal fibrosis and an altered hair cycle. The fibrotic phenotype correlated with a reduction in the potential of Sca1+ fibroblasts to undergo adipogenic differentiation ex vivo. Our findings indicate that Wnt/alpha-catenin signaling controls adipogenic cell fate within the lower dermis, which potentially contributes to the pathogenesis of fibrotic skin diseases.

2016-01-12 | GSE76751 | GEO

Single cell transcriptomics defines keratinocyte differentiation in avian scutate scales

Project description:Epidermal keratinocytes form cornified skin appendages such as scutate scales on the legs of birds. Here, we investigated the molecular pathways of keratinocyte differentiation in chicken scutate scales by single cell transcriptomics. We identified two distinct populations of differentiated keratinocytes. The first type of differentiated keratinocytes is characterized by mRNAs encoding scale-type corneous beta-proteins (CBPs), also known as beta-keratins and cysteine-rich keratins, indicating that these cells form hard scales. The second type of differentiated keratinocytes contains mRNAs encoding keratinocyte-type CBPs and cysteine-poor keratins, indicating that these cells form the soft interscale epidermis. Immunostaining with a newly raised antibody confirmed that keratin 9-like cysteine-rich 2 (KRT9LC2) or Hard Acid Sauropsid-specific 2 (HAS2) keratin, which is a marker of the first type of keratinocytes, is expressed in the suprabasal epidermal layers of scutate scales but not in interscale epidermis. Furthermore, mRNA of CTNN1B, previously implicated in scale placode formation, was enriched in differentiated scale keratinocytes, whereas genes involved in lipid metabolism, such as ELOVL4 and FADS1 were enriched in keratinocytes of the interscale epidermis. In conclusion, this study defines the gene expression programs that build the scutate scales and interscale epidermis of birds.

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