Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The Hay Wells Syndrome-Derived TAp63alphaQ540L Mutant Has Impaired Transcriptional and Cell Growth Regulatory Activity

ABSTRACT: p63 mutations have been associated with several human hereditary disorders characterized by ectodermal dysplasia such as EEC syndrome, ADULT syndrome and AEC syndrome . The location and functional effects of the mutations that underlie these syndromes reveal a striking genotype-phenotype correlation. Unlike EEC and ADULT that result from missense mutations in the DNA-binding domain of p63, AEC is solely caused by missense mutations in the SAM domain of p63. We report a study on the TAp63a isoform, the first to be expressed during development of the embryonic epithelia, and on its naturally occurring Q540L mutant derived from an AEC patient. To assess the effects of the Q540L mutation, we generated stable cell lines expressing TAp63a wt, DeltaNp63 alpha or the TAp63 alpha-Q540L mutant protein and used them to systematically compare the cell growth regulatory activity of the mutant and wt p63 proteins and to generate, by microarray analysis, a comprehensive profile of differential gene expression. We found that the Q540L substitution impairs the transcriptional activity of TAp63a and causes misregulation of genes involved in the control of cell growth and epidermal differentiation. Keywords: Hay Wells syndrome, TAp63alpha, genetic alteration, pp63 Q540L

ORGANISM(S): Homo sapiens

PROVIDER: GSE8646 | GEO | 2007/08/02

SECONDARY ACCESSION(S): PRJNA101835

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transcription profiling of human cell lines from Hay Wells Syndrome-Derived TAp63alphaQ540L mutant rveals impaired transcriptional and cell growth regulatory activity

Project description:p63 mutations have been associated with several human hereditary disorders characterized by ectodermal dysplasia such as EEC syndrome, ADULT syndrome and AEC syndrome . The location and functional effects of the mutations that underlie these syndromes reveal a striking genotype-phenotype correlation. Unlike EEC and ADULT that result from missense mutations in the DNA-binding domain of p63, AEC is solely caused by missense mutations in the SAM domain of p63. We report a study on the TAp63a isoform, the first to be expressed during development of the embryonic epithelia, and on its naturally occurring Q540L mutant derived from an AEC patient. To assess the effects of the Q540L mutation, we generated stable cell lines expressing TAp63a wt, DeltaNp63 alpha or the TAp63 alpha-Q540L mutant protein and used them to systematically compare the cell growth regulatory activity of the mutant and wt p63 proteins and to generate, by microarray analysis, a comprehensive profile of differential gene expression. We found that the Q540L substitution impairs the transcriptional activity of TAp63a and causes misregulation of genes involved in the control of cell growth and epidermal differentiation. Experiment Overall Design: Three biological replicates of not induced TAp63 alpha wt, three biological replicates of induced TAp63 alpha wt, three biological replicates of not induced TAp63Q540L alpha mutant and two biological replicates of induced TAp63Q540L alpha mutant

2008-06-16 | E-GEOD-8646 | biostudies-arrayexpress

DeltaNp63 silencing, DNA methylation shifts and epithelial mesenchymal transition resulted from TAp63 genome editing in squamous cell carcinoma [RRBS]

Project description:TP63 (p63) is strongly expressed in lower-grade carcinomas of head-and-neck, skin, breast, urothelium, etc. to maintain the well-differentiated phenotype. TP63 has two transcription start sites at exon 1 and exon 3’ to produce TAp63 and DeltaNp63 isoforms, respectively. The major protein, DeltaNp63alpha, functions as a core factor to organize super enhancers of genes essential for epidermal/craniofacial differentiation and for self-activation of DeltaNp63. To examine whether very weakly expressed TAp63 has a specific role, we disrupted exon 1 by CRISPR-Cas9 homology directed repair (HDR) in a head and neck squamous cell carcinoma (SCC) line. Surprisingly, TAp63 knockout cells, with either ‘monoallelic HDR and a frameshift deletion on the other allele’ or ‘biallelic HDR’, caused DeltaNp63 silencing. Loss of keratinocyte-specific gene expression, replacement of KRT5 with VIM, and transcriptional suppression of cell-cell and cell-matrix adhesion components indicated core events of epithelial mesenchymal transition. Most of the positively and negatively impacted genes including DeltaNp63 displayed local CpG methylation changes. Furthermore, DeltaNp63 expression was partially rescued by transfection of TAp63alpha, followed by incubation with DNA methyltransferase inhibitor Zebularine. This study suggests that TAp63 is indispensable for DeltaNp63 expression by which keratinocyte-specific epigenome is maintained in SCC.

2023-09-29 | GSE234979 | GEO

DeltaNp63 silencing, DNA methylation shifts and epithelial mesenchymal transition resulted from TAp63 genome editing in squamous cell carcinoma [microarray]

Project description:TP63 (p63) is strongly expressed in lower-grade carcinomas of head-and-neck, skin, breast, urothelium, etc. to maintain the well-differentiated phenotype. TP63 has two transcription start sites at exon 1 and exon 3’ to produce TAp63 and DeltaNp63 isoforms, respectively. The major protein, DeltaNp63alpha, epigenetically activates genes essential for epidermal/craniofacial differentiation, including DeltaNp63 itself. To examine whether weakly expressed TAp63 has a specific role, we disrupted exon 1 by CRISPR-Cas9 homology directed repair in a head and neck squamous cell carcinoma (SCC) line. Surprisingly, TAp63 knockout cells, either by monoallelic GFP cassette insertion paired with a frameshift deletion allele or by biallelic GFP cassette insertion, caused DeltaNp63 silencing. Loss of keratinocyte-specific gene expression, switching of intermediate filaments from KRT(s) to VIM, and suppression of cell-cell and cell-matrix adhesion components indicated core events of epithelial mesenchymal transition. Most of the positively and negatively impacted genes including DeltaNp63 displayed local DNA methylation changes. Furthermore, DeltaNp63 expression was partially rescued by transfection of TAp63alpha followed by incubation with DNA methyltransferase inhibitor Zebularine. TAp63, as a minor part of TP63 gene, may possibly be involved in the auto-activation mechanism of DeltaNp63 by which keratinocyte-specific epigenome is maintained in SCC.

2023-09-29 | GSE234978 | GEO

Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape

Project description:<p>Transcription factor p63 is a key regulator of epidermal keratinocyte proliferation and differentiation. Mutations in the p63 DNA-binding domain are associated with Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate (EEC) syndrome. Underlying molecular mechanism of these mutations however remain unclear. Here we characterized the transcriptome and epigenome of p63 mutant keratinocytes derived from EEC patients. The transcriptome of p63 mutant keratinocytes deviated from the normal epidermal cell identity. Epigenomic analyses showed an altered enhancer landscape in p63 mutant keratinocytes contributed by loss of p63-bound active enhancers and by unexpected gain of enhancers. The gained enhancers were frequently bound by deregulated transcription factors such as RUNX1. Reversing RUNX1 overexpression partially rescued deregulated gene expression and the altered enhancer landscape. Our findings identify an unreported disease mechanism whereby mutant p63 rewires the enhancer landscape and affects epidermal cell identity, consolidating the pivotal role of p63 in controlling the enhancer landscape of epidermal keratinocytes.</p>

| phs001737 | dbGaP

TAp63 in pancreas cancer predicts the squamous subtype and promotes a suppressive immune micromilleu

Project description:To evaluate the role of aberrant TAp63 in PDAC, we analyzed transcriptomics by RNAseq in the TAp63 and deltaNP63 over-expressing pancreatic cancer cells.

2022-11-22 | GSE218268 | 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

Late cornified envelope 1C (LCE1C) gene is a transcriptional target of TAp63.

Project description:As a member of the p53/p63/p73 family, p63 is a transcriptional regulator that induces apoptosis, cell cycle arrest, or senescence. TAp63 protein, a p53-like master transcriptional regulator, plays an essential role in epithelial development because p63-null mice are born alive but die shortly after birth due to developmental defects. However, its molecular mechanism remains elusive. We identified these phosphorylation sites during a search for the targets of Cyclin G-associated kinase (GAK) in vitro. LCE1C was drastically upregulated by doxycycline-dependent expression of Myc-TAp63 wild-type (WT) proteins, but not non-phosphorylatable Myc-TAp63-T46A/T281A (AA) proteins.

2018-03-22 | GSE94635 | GEO

p63 cooperates with CTCF to modulate chromatin accessibility and architecture in skin keratinocytes

Project description:Here we integrated multi-omics profiles including transcriptomics, DNA accessibility and capture Hi-C data to explore how p63 shapes local chromatin architecture in skin keratinocytes isolated from EEC syndrome patients. Surprisingly, we observed decreased chromatin accessibility in a number of DNA looping nodes which were co-mediated by p63 and CTCF. Our findings not only identified a new aspect of the bookmark function of p63, but also shed light on the disease mechanism underlined p63 dysfunction. Therefore, we propose p63 as a spatial genome organizer by modulating a subset of DNA loops with CTCF and therefore fine-tuning transcription programs required for skin keratinocytes.

2019-06-21 | GSE123711 | GEO

p63 ChIP-seq analysis comparing WT, TAp63-null, and DNp63-null primary murine keratinocytes

Project description:We performed a ChIP-seq analysis characterizing the p63 binding sites in primary keratinocytes obtained from E18.5 mice of 3 different genotypes (WT, TAp63-/-, and ΔNp63-/-). We aimed to identify the specific genomic regions bound by TAp63 and ΔNp63 in physiological conditions.

2018-03-20 | GSE79448 | GEO

ChIP-seq analysis comparing WT, TAp63-/-, and ΔNp63-/- primary murine keratinocytes

Project description:The p53 family member TP63 encodes two sets of isoforms, TAp63 and ∆Np63 isoforms, which are characterized by different N-termini and have diverse biological functions in epidermal morphogenesis and in cancer. In the skin, where their activities are best characterized, TAp63 prevents premature aging by regulating cellular senescence and genomic stability of stem cells, while ∆Np63 controls terminal differentiation of the basal cells in the epidermis. This functional diversity is surprising given that these isoforms share a high degree of similarity, including an identical DNA binding domain. To understand the mechanisms involved in the transcriptional programs leading to these diverse biological functions, we performed genome-wide analyses using p63-ChIP-seq and RNA-seq of TAp63-/- and ∆Np63-/- compared to wild-type primary mouse epidermal cells. Our data indicate that TAp63 and ∆Np63 recognize significantly different response elements on DNA and can physically and functionally interact with distinct transcription factors for the downstream regulation of their target genes. Our findings unveil previously uncharacterized transcriptomes activated by the p63 isoforms to regulate diverse biological functions in epidermal morphogenesis and homeostasis and cancer.

2023-12-06 | GSE147723 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data