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ABSTRACT:
PROVIDER: PRJNA115081 | ENA |
REPOSITORIES: ENA
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Project description:Skin and bladder epithelia form effective permeability barriers through the activation of distinct differentiation gene programs. Employing a genome-wide gene expression study, we identified transcription regulators whose expression correlates highly with that of differentiation markers both in bladder and skin, including the Grainyhead factor Get1/Grhl3, already known to be important for epidermal barrier formation. In the bladder, Get1 is most highly expressed in the differentiated umbrella cells and its mutation in mice leads to a defective bladder epithelial barrier formation due to failure of apical membrane specialization. Genes encoding components of the specialized urothelial membrane, the uroplakins, were downregulated in Get1-/- mice. At least one of these genes, Uroplakin II, is a direct target of Get1. The urothelial-specific activation of the Uroplakin II gene is due to selective binding of Get1 to the Uroplakin II promoter in urothelial cells, most likely regulated by histone modifications. These results demonstrate a key role for Get1 in urothelial differentiation and barrier formation.
2009-05-20 | GSE15772 | GEO
Project description:Skin and bladder epithelia form effective permeability barriers through the activation of distinct differentiation gene programs. Employing a genome-wide gene expression study, we identified transcription regulators whose expression correlates highly with that of differentiation markers both in bladder and skin, including the Grainyhead factor Get1/Grhl3, already known to be important for epidermal barrier formation. In the bladder, Get1 is most highly expressed in the differentiated umbrella cells and its mutation in mice leads to a defective bladder epithelial barrier formation due to failure of apical membrane specialization. Genes encoding components of the specialized urothelial membrane, the uroplakins, were downregulated in Get1-/- mice. At least one of these genes, Uroplakin II, is a direct target of Get1. The urothelial-specific activation of the Uroplakin II gene is due to selective binding of Get1 to the Uroplakin II promoter in urothelial cells, most likely regulated by histone modifications. These results demonstrate a key role for Get1 in urothelial differentiation and barrier formation.
2009-05-20 | GSE15770 | GEO
Project description:Skin and bladder epithelia form effective permeability barriers through the activation of distinct differentiation gene programs. Employing a genome-wide gene expression study, we identified transcription regulators whose expression correlates highly with that of differentiation markers both in bladder and skin, including the Grainyhead factor Get1/Grhl3, already known to be important for epidermal barrier formation. In the bladder, Get1 is most highly expressed in the differentiated umbrella cells and its mutation in mice leads to a defective bladder epithelial barrier formation due to failure of apical membrane specialization. Genes encoding components of the specialized urothelial membrane, the uroplakins, were downregulated in Get1-/- mice. At least one of these genes, Uroplakin II, is a direct target of Get1. The urothelial-specific activation of the Uroplakin II gene is due to selective binding of Get1 to the Uroplakin II promoter in urothelial cells, most likely regulated by histone modifications. These results demonstrate a key role for Get1 in urothelial differentiation and barrier formation.
2009-05-20 | GSE15768 | GEO
Project description:This study aimed to investigate the highly-differentiated urothelial apical surface glycome. The functions of the mammalian urothelium, lining the majority of the urinary tract and providing a barrier against toxins in urine, are dependent on the correct differentiation of urothelial cells, relying on protein expression, modification and complex assembly to regulate the formation of multiple differentiated cell layers. Protein glycosylation, a poorly studied aspect of urothelial differentiation, contributes to the apical glycome and is implicated in the development of urothelial diseases. To enable surface glycome characterization, we have developed a method to collect the tissue apical surface N- and O-glycans. A simple, novel device using basic laboratory supplies was developed for enzymatic shaving of the luminal urothelial surface, with subsequent release and mass spectrometric analysis of apical surface O- and N-glycans; the first normal mammalian urothelial N-glycome to be defined. Trypsinization of superficial glycoproteins was tracked using immunolabelling of the apically-expressed uroplakin 3a protein to optimize enzymatic release, without compromising the integrity of the superficial urothelial layer. The approach developed for releasing apical tissue surface glycans allowed comparison with the N-glycome of total porcine urothelial cells, and thus identification of apical surface glycans as candidates implicated in urothelial barrier function.
2021-07-19 | MSV000087851 | MassIVE
Project description:Urothelium forms a distensible yet impermeable barrier, senses and transduces stimuli, and defends the urinary tract from mechanical, chemical and bacterial injuries. Biochemical and genetic labeling studies support the existence of one or more progenitor populations with the capacity to rapidly regenerate the urothelium following injury, but slow turnover, a low mitotic index, and inconsistent methodologies obscure progenitor identity. The progenitor properties of basal Keratin 5 urothelial cells (K5-UC) have been previously investigated, but those studies focused on embryonic or adult bladder urothelium. Urothelium undergoes desquamation and apoptosis after birth, which requires postnatal proliferation and restoration. Therefore, we mapped the fate of bladder K5-UCs across postnatal development/maturation and following administration of cyclophosphamide to measure homeostatic and reparative progenitor capacities, respectively. In vivo studies demonstrate that basal K5-UCs are age-restricted progenitors in neonates and juveniles, but not in adult mice. Neonatal K5-UCs retain a superior progenitor capacity in vitro, forming larger and more differentiated urothelial organoids than adult K5-UCs. Accordingly, K5-UC transcriptomes are temporally distinct, with enrichment of transcripts associated with cell proliferation and differentiation in neonates. Induction of urothelial proliferation is sufficient to restore adult K5-UC progenitor capacity. Our findings advance the understanding of urothelial progenitors and support a linear model of urothelial formation and regeneration, which may have significant impact on therapeutic development or tissue engineering strategies.
2024-01-03 | GSE248463 | GEO
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
Project description:Essential to terrestrial life is the formation of a competent skin barrier that prevents desiccation and entry by harmful substances. A tightly orchestrated series of cellular changes is required for the proper formation of the epidermal permeability barrier. These changes occur in the context of the commensal skin microbiota. Using germ free mice and antibiotic depletion models, we demonstrate the microbiota is necessary for proper differentiation and repair of the barrier. These effects were mediated by keratinocyte signaling through the aryl hydrocarbon receptor (AHR), a xenobiotic receptor that also regulates epidermal differentiation. Murine skin lacking keratinocyte AHR was more susceptible to infection by S. aureus and increased pathology in a model of atopic dermatitis. Topical colonization with a defined consortium of human skin commensals restored barrier competence in germ free skin and during epicutaneous sensitization; these effects were dependent on keratinocyte AHR. We reveal a fundamental role for the commensal skin microbiota in directing skin barrier formation and repair through the AHR, with far-reaching implications for the numerous skin disorders characterized by disrupted epidermal differentiation and/or barrier competence.
2021-03-31 | GSE162925 | GEO
Project description:Disrupted skin barrier due to altered keratinocyte differentiation is common in pathologic conditions such as atopic dermatitis, ichthyosis and psoriasis. However, the molecular cascades governing keratinocyte terminal differentiation are still poorly understood. We have previously demostrated that a dominante mutation in ZNF750 leads to a clinical phenotype that reminiscent of psoriasis and seborrehic dermatitis. We defined ZNF750 as a nuclear effector that is atrongly activated in and essiential for keratinocyte terminal differentiation. ZNF750 knockdown in HaCaT keratinocytes markedly reduced the expression of epidermal late differentiation markers, including gene subsets of epidermal differentiation complex and skin barrier formation such as FLG, LOR, SPINK5, ALOX12B and DSG1, known to be mutated in various human skin diseases. Furthermore, ZNF750 over-expression in undifferentiated cells induced terminal differentiation genes. Thus, ZNF750 is a regulator of keratinocyte terminal differnetiation, and with its downstream targets can serve in future elucidation of therapeutics for common disease of skin barrier Gene expression analysis: To determine the differentaition signature for HaCaT keratinocytes, with ZNF750 gene silencing, total RNA was isolated in biologic triplicates from cells induced to differentiate for twelve days and hybridized to Affymerix Human Gene 1.0 ST arrays.
2012-09-24 | E-GEOD-38039 | biostudies-arrayexpress
Project description:We find that Pparg is a master regulator of cell specification during urothelial homeostasis, driving a luminal differentiation program via retinoid signaling. Interestingly, expression of activated Pparg in basal cells only drives tumor formation when they are in an activated state, that are in an activated state, induces formation of luminal tumors with papillary morphology, Expression of an activated form of Pparg induces basal cells at homeostasis, to differentiate directly into luminal cells. In a BBN mouse model which produces basal subtypes tumors in wild type animals, activated Pparg drives formation of luminal tumors, suggesting that this transcription factor is a master regulator of luminal differentiation, as has been suggested from in vitro studies.
2021-09-22 | GSE172656 | GEO
Project description:The cornified outer layer of epidermis (stratum corneum) is our major extra-pulmonary barrier to the environment. This layer results from a well-orchestrated program of terminal differentiation producing corneocytes filled primarily with keratin intermediate filaments tightly connected by disulfide bonding. This cytoskeleton is interconnected to an isopeptide cross-linked protein envelope at the cell periphery stabilized by transglutaminase cross-linking.The envelope serves as a scaffold for deposition of the lipid barrier containing w-OH-ceramides secreted from inside the maturing keratinocytes.That defects in the transglutaminase gene TGM1 are a major cause of autosomal recessive congenital ichthyosis testifies to the importance of proper envelope formation for barrier function.
2018-12-19 | MSV000083265 | MassIVE