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Unknown,Transcriptomics,Genomics,Proteomics

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

ABSTRACT: 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

ORGANISM(S): Homo sapiens

SUBMITTER: Kun Qu

PROVIDER: E-GEOD-33571 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Disrupted transcripitonal network in ΔNp63 AEC tissue model [gene expression]

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.

2012-06-18 | GSE33495 | GEO

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

2012-06-18 | GSE33571 | GEO

Disrupted transcripitonal network in ΔNp63 AEC tissue model [gene expression]

2012-06-17 | E-GEOD-33495 | biostudies-arrayexpress

Disrupted transcripitonal network in ΔNp63 AEC tissue model

Project description:This SuperSeries is composed of the following subset Series: GSE33495: Disrupted transcripitonal network in ΔNp63 AEC tissue model [gene expression] GSE33571: Disrupted transcriptional network in ΔNp63 AEC tissue model [ChIP-Seq] Refer to individual Series

2012-06-17 | E-GEOD-33572 | biostudies-arrayexpress

AFF1-HEXIM1 cooperation suppresses rapid-response differentiation initiators to enforce epidermal progenitor maintenance

Project description:In this study we identified an essential role of the SEC, a crucial regulator of Pol II dynamics, in repressing differentiation for epidermal progenitor maintenance. This repression of differentiation is specifically mediated by the scaffold protein AFF1, but not AFF4. Mechanistically, we find that AFF1-SEC associates with the HEXIM1-containing inactive-PTEFb to directly repress a group of rapid-response genes, which feature robust Pol II pausing near their promoters in the progenitor state. De-repression of these genes occurs within 3 hours of SEC-PTEFb disruption by the peptidomimetic inhibitors. These rapid-response genes include the transcription factor ATF3. Increased ATF3 level is sufficient to promote the expression of key differentiation activators, such as PRDM1, OVOL1, GRHL3 and ZNF750. Furthermore, we find that the dissociation of inactivate P-TEFb from SEC mediates the earliest events of PKC signaling, in triggering epidermal differentiation.

2022-06-24 | GSE182959 | GEO

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 Drives Terminal Epidermal Differentiation via Induction of Klf4

2012-02-15 | GSE32685 | GEO

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

GRHL3 chromatin binding and the super-enhancer landscape are reorganized in different functional states of epidermal keratinocytes

Project description:While the genomic mechanisms underlying progressive, irreversible cell lineage commitments are well-studied, we know little about the chromatin changes during transient cell states such as cell migration. Interestingly, a large number of SEs in NHEK-D and NHEK-M overlap genes encoding transcription factors with important roles in promotion of epidermal differentiation, including GRHL3, TP63, RUNX1, NOTCH3 and FOS. To test the role of these SE-associated transcription factors in a systematic manner, and to place GRHL3 in the context of other keratinocyte differentiation regulators, we used siRNAs to individually knock down GRHL3 and 50 other transcriptional regulators in NHEK-D. These transcriptional regulators were selected based on expression changes during human keratinocyte differentiation. Many have been previously implicated in epidermal differentiation in mice and humans; the genes encoding 22 of them are associated with SEs. To assess the effect of the knockdowns on keratinocyte differentiation, we monitored the expression of approximately 14,000 genes with custom-made Agilent microarrays. Among the 14,000 genes whose expression we monitored were all genes expressed in human keratinocytes and all transcriptional regulators. This 51 x 14,000 gene expression matrix provided a rich dataset to explore gene regulatory networks in epidermal differentiation.

2017-04-12 | GSE86193 | GEO

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