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ZNF750 Drives Terminal Epidermal Differentiation via Induction of Klf4

ABSTRACT: Disrupted differentiation is a hallmark of numerous diseases, which in epidermis alone impact >25% of the population. In a search for dominant mediators of differentiation, we defined a requirement for the ZNF750 nuclear protein in terminal epidermal differentiation. ZNF750 controlled genes mutated in numerous human skin diseases, including FLG, LOR, LCE3B, ALOXE3, and SPINK5. ZNF750 potently induced progenitor differentiation via an evolutionarily conserved C2H2 zinc finger motif. The epidermal master regulator, p63, bound the ZNF750 promoter and was necessary for its induction. ZNF750 restored differentiation to p63-deficient tissue, suggesting it acts downstream of p63. A search for functionally important ZNF750 targets via analysis of ZNF750-regulated genes identified KLF4, a transcription factor that activates late epidermal differentiation genes. ZNF750 binds the Klf4 promoter and controls its expression. ZNF750 thus provides a direct link between a tissue-specifying factor, p63, and an effector of terminal differentiation, Klf4, and represents a potential future target for disorders of this process.

ORGANISM(S): Homo sapiens

PROVIDER: GSE32685 | GEO | 2012/02/15

SECONDARY ACCESSION(S): PRJNA146897

REPOSITORIES: GEO

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ZNF750 Drives Terminal Epidermal Differentiation via Induction of Klf4

Project description:Disrupted differentiation is a hallmark of numerous diseases, which in epidermis alone impact >25% of the population. In a search for dominant mediators of differentiation, we defined a requirement for the ZNF750 nuclear protein in terminal epidermal differentiation. ZNF750 controlled genes mutated in numerous human skin diseases, including FLG, LOR, LCE3B, ALOXE3, and SPINK5. ZNF750 potently induced progenitor differentiation via an evolutionarily conserved C2H2 zinc finger motif. The epidermal master regulator, p63, bound the ZNF750 promoter and was necessary for its induction. ZNF750 restored differentiation to p63-deficient tissue, suggesting it acts downstream of p63. A search for functionally important ZNF750 targets via analysis of ZNF750-regulated genes identified KLF4, a transcription factor that activates late epidermal differentiation genes. ZNF750 binds the Klf4 promoter and controls its expression. ZNF750 thus provides a direct link between a tissue-specifying factor, p63, and an effector of terminal differentiation, Klf4, and represents a potential future target for disorders of this process. Gene expression analysis: To establish a differentiation signature for primary human keratinocytes, with ZNF750-depleted, and Klf4-depleted, total RNA was isolated in biologic duplicate from cells in different conditions and hybridized to Affymetrix HG-U133 2.0 Plus arrays.

2012-02-15 | E-GEOD-32685 | 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 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

Disrupted transcriptional network in ΔNp63 AEC tissue model [ChIP-Seq]

Project description:The transcriptional basis for disrupted epidermal differentiation arising from TP63 AEC mutations remains to be elucidated. Here we present an organotypic model of AEC dysfunction that phenocopies differentiation defects observed in AEC patient skin. Transcriptional analysis of model AEC tissue revealed impaired induction of differentiation regulators, including OVOL1, GRHL3, KLF4, PRDM1 and ZNF750. Genome wide binding analyses of TP63 during epidermal differentiation showed direct binding of OVOL1, GRHL3, and ZNF750 promoters suggesting AEC mutants prevent normal activation of these targets by direct transcriptional interference. Remarkably, exogenous ZNF750 restores impaired epidermal differentiation caused by AEC mutation. Thus, repression of ZNF750 is central to disrupted epidermal differentiation in model AEC tissue. ChIP-Seq analysis: Examination of p63 binding in proliferating and differentiating human keratinocytes

2012-06-18 | E-GEOD-33571 | 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

ZNF750 Interacts with KLF4 and Specific Chromatin Regulators to Control Epidermal Differentiation

Project description:Here we find that ZNF750 activates epidermal differentiation genes and represses progenitor genes as part of two distinct protein complexes Identified genomic binding sites of ZNF750 and its interacting proteins

2014-09-11 | E-GEOD-57702 | biostudies-arrayexpress

ZNF750 is a lineage-specific tumor suppressor in squamous cell carcinoma [UMSCC1]

Project description:ZNF750 controls epithelial homeostasis by regulating epidermal-differentiation genes, a role underscored by its pathogenic mutations in esophageal squamous cell cancers (SCCs). However, the precise role of ZNF750 in SCC cell biology remains unclear. In this study, we report that ZNF750 is exclusively deleted, mutated and underexpressed in human SCCs, and low ZNF750 expression is associated with poor survival. Restoration of wildtype, but not mutant ZNF750 protein uniquely inhibited the malignant phenotype of SCC cells both in vitro and in vivo. Notably, ZNF750 promoted the expression of a LncRNA (TINCR) which mediated both cancer-inhibition and differentiation-induction effects of ZNF750. In addition, ZNF750 potently suppressed cell migration by directly inhibiting the transactivation of LAMC2. Together, our findings characterize ZNF750 as a crucial SCC-specific suppressor and uncover its novel anticancer-associated functions.

2016-08-25 | GSE86014 | GEO

ZNF750 is a lineage-specific tumor suppressor in squamous cell carcinoma [UMSCC1]

2016-08-25 | E-GEOD-86014 | biostudies-arrayexpress

ZNF750 is a lineage-specific tumor suppressor in squamous cell carcinoma [CaSki]

2016-08-25 | GSE86013 | GEO

ZNF750 Interacts with KLF4 and Specific Chromatin Regulators to Control Epidermal Differentiation

Project description:Here we find that ZNF750 activates epidermal differentiation genes and represses progenitor genes as part of two distinct protein complexes

2014-09-11 | GSE57702 | GEO

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