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Genome-wide analysis of histone modifications H3K27ac, H3K4me3, and H3K4me1 in migrating primary human epidermal keratinocytes (NHEK)

ABSTRACT: The epidermis is a stratified squamous epithelium that serves to protect the body from dehydration, absorption of chemicals, and invasion of pathogens. It derives from the surface ectoderm during the later stages of mammalian embryonic development. In a stratified squamous epithelium cells of the basal layer contain proliferative potential. As they divide and move upward in the tissue, they progressively differentiate, and activate the gene expression program required to create a barrier; eventually, cells in the uppermost layer are sloughed off from the surface of the epidermis. This system requires continual replacement of differentiating cells from the basal layer. Such a process requires very precise regulation of gene expression to balance proliferation and differentiation and maintain a functioning epithelium. A number of transcription factors are known to be crucial to maintaining this balance; among these are p63, Notch, c-myc, Klf4, and Grhl3. These factors interact in a complex epidermal differentiation network, where the contributions of each factor provide balance and precision to the process of differentiation. When the epidermal barrier is breached due to wounding, a cascade of cytokines and other signaling molecules activate a wound healing program of gene expression, inducing everything from blood clotting, immune cell infiltration of the skin, regrowth of blood and lymph vessels, and the coordinated keratinocyte migration into the center of the wound followed by stratification, all of which is required to regenerate the lost tissue.

ORGANISM(S): Homo sapiens

PROVIDER: GSE68075 | GEO | 2017/04/12

SECONDARY ACCESSION(S): PRJNA281873

REPOSITORIES: GEO

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Genome-wide analysis of histone modifications H3K27ac, H3K4me3, and H3K4me1 in differentiating primary human epidermal keratinocytes (NHEK)

Project description:The epidermis is a stratified squamous epithelium that serves to protect the body from dehydration, absorption of chemicals, and invasion of pathogens. In the epidermis, cells of the basal layer contain proliferative potential. As they divide and move upward in the tissue, they progressively differentiate, and activate the gene expression program required to create a barrier; eventually, cells in the uppermost layer are sloughed off from the surface of the epidermis. This system requires continual replacement of differentiating cells from the basal layer. Such a process requires very precise regulation of gene expression to balance proliferation and differentiation and maintain a functioning epithelium. Epigenetic mechanisms of gene regulation, including DNA methylation and histone modification have been shown to play a major role in tissue development and wound healing. To identify regulatory regions in differentiating epidermal cells, we performed ChIP-Seq with antibodies to H3K4me1, and H3K4me3 at 24 hours after induction of differentiation to complement publicly available ENCODE data for these marks in undifferentiated NHEK. With this data, we were able to identify enhancers, defined by the presence of high levels of H3K4me1 and H3K27ac, and low levels of H3K4me3. We identified approximately 20,000 of these regions each in undifferentiated and differentiated keratinocytes. Approximately 20 percent of these regions were shared between the two conditions, while about 30 and 43 percent were unique to differentiated and undifferentiated keratinocytes, respectively.

2016-04-24 | GSE68257 | GEO

TGM1 interaction partners identification reveals possible TGM1 posttranslational modifiers

Project description:TGM1 is an enzyme that cross-links structural proteins in the uppermost granular layer of the epidermis to form cornified envelopes. Cornified envelopes ensure functional stratum corneum and epidermal barrier formation. It has been suggested that the activity of TGM1 is regulated on a posttranslational level. To identify endogenous TGM1 interactors, Virotrap has been performed.

2024-01-26 | PXD045105 | Pride

Transcription profiling of mouse epidermis of Tcfap2c mutant and control skin at embryonic day 16.5

Project description:The development of the epidermis, a stratified squamous epithelium, is dependent on the regulated differentiation of keratinocytes. Differentiation begins with the initiation of stratification, a process tightly controlled through proper gene expression. AP-2Î³ is expressed in skin and previous research suggested a pathway where p63 gene induction results in increased expression of AP-2Î³ which in turn is responsible for induction of K14. This study uses a conditional gene ablation model to further explore the role of AP-2Î³ in skin development. Mice deficient for AP-2Î³ exhibited delayed expression of p63, K14, and K1, key genes required for development and differentiation of the epidermis. In addition, microarray analysis of E16.5 skin revealed delayed expression of additional late epidermal differentiation genes: filaggrin, repetin and secreted Ly6/Plaur domain containing 1, in mutant mice. The genetic delay in skin development was further confirmed by a functional delay in the formation of an epidermal barrier. These results document an important role for AP-2Î³ in skin development, and reveal the existence of regulatory factors that can compensate for AP-2Î³ in its absence. Experiment Overall Design: Skin samples were collected from 3 Tcfap2c and 3 control animals at embryonic day 16.5.

2008-06-11 | E-GEOD-10175 | biostudies-arrayexpress

Grhl3 is essential for epidermal barrier repair from both physical and immune injury, relevance to lesional skin disease

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

Mutant p63 disrupts the key specification switch from the multipotent cell state to stratified epithelia during epithelial differentiation/in ectodermal dysplasia disorders

Project description:Transcription factor p63 is a key regulator of stratified epithelia. In humans mutations in p63 are associated with developmental disorders that manifest defects in stratified epithelia including the epidermis. We established an epidermal commitment model using human pluripotent stem cells (PSCs) and characterized differentiation defects of PSCs carrying p63 mutations. Transcriptome analyses revealed distinct phases of epidermal commitment, multipotent simple epithelial, basal stratified epithelial and mature epidermal fates. Differentiation defects of p63 mutant PSCs occurred during the specification switch from the simple epithelium to the basal stratified epithelial fate. Single-cell transcriptome and pseudotime analyses identified enhanced mesodermal signatures associated with the deviated commitment route of p63 mutant PSCs. Repressing mesodermal differentiation improved epidermal commitment of PSCs. Our study demonstrate that p63 is required for specification of stratified epithelia but not sufficient for epidermal maturation. It provides insights into disease mechanisms underlying defects of stratified epithelia caused by p63 mutations.

2019-08-19 | GSE120107 | GEO

Comparison of gene expression in the epidermis of Tcfap2c mutant and control skin at embryonic day 16.5

Project description:The development of the epidermis, a stratified squamous epithelium, is dependent on the regulated differentiation of keratinocytes. Differentiation begins with the initiation of stratification, a process tightly controlled through proper gene expression. AP-2γ is expressed in skin and previous research suggested a pathway where p63 gene induction results in increased expression of AP-2γ which in turn is responsible for induction of K14. This study uses a conditional gene ablation model to further explore the role of AP-2γ in skin development. Mice deficient for AP-2γ exhibited delayed expression of p63, K14, and K1, key genes required for development and differentiation of the epidermis. In addition, microarray analysis of E16.5 skin revealed delayed expression of additional late epidermal differentiation genes: filaggrin, repetin and secreted Ly6/Plaur domain containing 1, in mutant mice. The genetic delay in skin development was further confirmed by a functional delay in the formation of an epidermal barrier. These results document an important role for AP-2γ in skin development, and reveal the existence of regulatory factors that can compensate for AP-2γ in its absence. Keywords: genetic modification

2008-01-16 | GSE10175 | GEO

Transcription profiling of human keratinocytes used in a small molecule screen to identify inducers of epidermal keratinocyte differentiation

Project description:An essential function of the human epidermis is the maintenance of a protective barrier against the environment. As a consequence, keratinocytes, which make up this layer of the skin, undergo an elaborate process of self-renewal, terminal differentiation and cell death. Misregulation of these processes can lead to several human diseases including psoriasis and basal cell and squamous cell carcinomas. To identify novel regulators of keratinocyte differentiation, a cell-based screen of small molecule libraries was carried out for molecules that induce terminal differentiation of normal human epidermal keratinocytes (NHEKs). One class of molecules was identified, the 2-(3,4,5-trimethoxy-phenylamino)-pyrrolo[2,3-d]pyrimidines, which were shown to induce differentiation of epidermal progenitor cells to terminally differentiated keratinocytes. These molecules serve as useful mechanistic probes of the cellular differentiation programs that regulate the formation and homeostasis of the epidermis, and may lead to novel therapeutic approaches for the treatment of skin hyperproliferative disorders. Experiment Overall Design: samples were taken from duplicate treatments of cells with DMSO or PP-2 (compound 9) at various time points

2009-04-10 | E-GEOD-6932 | biostudies-arrayexpress

Transcription profiling of mouse skins of embryos lacking Grainyhead-like epithelial transactivator (Get-1)

Project description:Defective permeability barrier is an important feature of many skin diseases and causes mortality in premature infants. To investigate the control of barrier formation, we characterized the epidermally expressed Grainyhead-like epithelial transactivator (Get-1)/Grhl3, a conserved mammalian homologue of Grainyhead, which plays important roles in cuticle development in Drosophila. Get-1 interacts with the LIM-only protein LMO4, which is co-expressed in the developing mammalian epidermis. The epidermis of Get-1(-/-) mice showed a severe barrier function defect associated with impaired differentiation of the epidermis, including defects of the stratum corneum, extracellular lipid composition and cell adhesion in the granular layer. The Get-1 mutation affects multiple genes linked to terminal differentiation and barrier function, including most genes of the epidermal differentiation complex. Get-1 therefore directly or indirectly regulates a broad array of epidermal differentiation genes encoding structural proteins, lipid metabolizing enzymes and cell adhesion molecules. Although deletion of the LMO4 gene had no overt consequences for epidermal development, the epidermal terminal differentiation defect in mice deleted for both Get-1 and LMO4 is much more severe than in Get-1(-/-) mice with striking impairment of stratum corneum formation. These findings indicate that the Get-1 and LMO4 genes interact functionally to regulate epidermal terminal differentiation. Experiment Overall Design: The same region of the mouse back skin was excised from three Get1 +/+ and three Get1 â/â mice at e18.5.

2007-12-13 | E-GEOD-7381 | biostudies-arrayexpress

Role of Znf750 in skin development

Project description:The skin epidermis is a constantly renewing stratified epithelial tissue that provides essential protective barrier functions. The major barrier is at the outermost layers of the epidermis, formed by terminally differentiated keratinocytes reinforced by proteins and lipids of their cornified envelope (CE), and disruptions to this process characterizes common skin disorders. ZNF750 is an epithelial transcription factor essential for in vitro keratinocyte differentiation, whose autosomal dominant mutation in humans causes psoriasis-like skin disease. Here, we report epidermal-specific Znf750 conditional knockout mouse model utilized to uncover the role of Znf750 in epidermal development. We show that deletion of Znf750 in the developing skin does not block epidermal differentiation, suggesting in vivo compensatory feedback mechanisms, yet results in impaired barrier function and perinatal lethality. Molecular dissection uncovered ultrastructural defects in the differentiated layers of the epidermis, accompanied by alterations in the expression of ZNF750-dependent genes encoding for key proteins and lipids involved in CE formation, including gene subsets known to be mutated in skin disease with impaired barrier function.

2023-08-01 | GSE235032 | GEO

Grhl3 is essential for epidermal barrier repair from both physical and immune injury, relevance to lesional skin disease

2014-09-01 | GSE52648 | GEO

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