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ZFP750 regulates skin lipid metabolism and cutaneous barrier

ABSTRACT: A life-essential function of the epidermis is to provide a physical barrier that prevents the loss of water and electrolytes. Essential mediators of this permeability barrier function include ceramides, cholesterol and very long chain fatty acids. Accordingly, their alteration may lead to distinct human conditions, including psoriasis or atopic dermatitis. Recently, a frameshift mutation in the human ZNF750 gene, that encodes for a zinc finger transcription factor, causing a seborrhea-like dermatitis with psoriasiform element, has brought ZNF750 as a key element for the maintenance of the epidermal tissue homeostasis. To clarify this hypothesis, with its underlying molecular mechanism, we generated a novel mouse knockout by deleting exon 2. Here, we show that genetic deletion of the mouse homolog ZFP750 results in loss of epidermal permeability barrier function. ZFP750-/- mice die shortly after birth, within 12 hours. In the stratum corneum of ZFP750-/- mice levels of ceramides, nonpolar lipids and intercellular lipid lamellae are significantly reduced. The alteration of the epidermal lipid homeostasis is directly linked to the transcriptional activity of ZFP750. Indeed, in addition to epidermal differentiation genes, ZFP750 directly and/or indirectly regulates the expression of nearly 50 crucial enzymes in the biosynthesis of ceramides, such as SPTLC1, DGAT2, SMPD3, ELOVL7 and DEGS2. Overall, our study identifies the transcription factor ZFP750 as a master regulator of lipid biosynthesis and epidermal homeostasis and may contribute to our understanding of the pathogenesis of several human skin diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE220813 | GEO | 2023/05/03

REPOSITORIES: GEO

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ZNF750 in late keratinocyte differentiation

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

ZNF750 in late keratinocyte differentiation

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 demonstrated that a dominant mutation in ZNF750 leads to a clinical phenotype that reminiscent of psoriasis and seborrheic dermatitis. We defined ZNF750 as a nuclear effector that is strongly activated in and essential 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 differentiation, and with its downstream targets can serve in future elucidation of therapeutics for common disease of skin barrier

2012-09-24 | GSE38039 | GEO

Loss of MPZL3 Function Causes Seborrheic Dermatitis-like Phenotype in Mice

Project description:Seborrheic Dermatitis (SD) is a common inflammatory skin disorder. In this study, we demonstrated SD-like clinical features with associated histology in the Mpzl3 knockout(-/-) mice. Mpzl3-/- skin showed increased macrophage and CD4+ lymphocyte infiltration, however adaptive immunity was not required for the onset of skin inflammation. Furthermore, we detected epidermal barrier defects as suggested by increased dye permeability in Mpzl3-/- embryos and altered gene expression by microarray analysis in pup skin. Taken together, these findings suggest MPZL3 plays an essential role in epidermal differentiation and barrier function, and underscore the interplay between epidermal barrier and immunity in SD. The SD-like clinical and histologic features in the Mpzl3-/- mice also resemble those in patients carrying a frame-shift mutation in ZNF750, a key regulator of epidermal differentiation and a transcriptional activator of the MPZL3 gene. Therefore, we conclude that the ZNF750/MPZL3 pathway plays a critical role in the pathogenesis of SD, and a better understanding of skin inflammation and barrier restoration in the Mpzl3-/- mice will provide insight into the pathogenesis and treatment/prevention of recurrent SD.

2018-07-27 | GSE117755 | GEO

PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis

Project description:Mutations in PNPLA1 (patatin-like phospholipase domain containing 1) cause autosomal recessive congenital ichthyosis, but the mechanism involved remains unclear. Here we show that PNPLA1, an enzyme expressed in highly differentiated keratinocytes, plays a crucial role in the biosynthesis of acylceramide, a lipid component essential for skin barrier function. Pnpla1-deficient mice showed neonatal lethality due to epidermal permeability barrier defects with severe transepidermal water loss, decreased intercellular lipid lamellae in the stratum corneum, and impaired terminal differentiation of keratinocytes. In Pnpla1–/– epidermis, three unique linoleate-containing lipids, including acylceramides, acylglucosylceramides and (O-acyl)-ω-hydroxy fatty acids, were almost absent with reciprocal increases in their precursors ω-hydroxy (glucosyl)ceramides and ω-hydroxy fatty acids, indicating that PNPLA1 catalyzes the ω-O-esterification step with linoleic acid to form acylceramides. Our results suggest that PNPLA1 represents the missing piece in the process of acylceramide biosynthesis required for establishment of a permeability barrier.

2016-12-23 | GSE87682 | GEO

Knockouts of both Vitamin D receptor (VDR) and its coactivator Med1 enhance epidermal permeability barrier function

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2020-09-14 | GSE157887 | GEO

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.

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Conditional keratinocyte-specific ADAM17 knockout in mice alters skin homeostasis

2012-06-21 | GSE38830 | GEO

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Proteomic analysis of small extracellular vesicles (sEVs) derived from primary keratinocytes cultured in different calcium concentrations, treated with a peanut allergen extract and atopic dermatitis (AD)-relevant cytokines

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2022-06-07 | PXD031729 | Pride

Conditional keratinocyte-specific ADAM17 knockout in mice alters skin homeostasis

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