Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

ΔNp63-Senataxin circuit controls keratinocyte differentiation by promoting the transcriptional termination of epidermal genes

ABSTRACT: ΔNp63, a master regulator of epithelial biology, is involved in regulating epithelial stem cell function, maintaining the integrity of stratified epithelial cells and committing epidermal cells to the differentiation program. To this end, ΔNp63 exploits several direct mechanisms. Here, we elucidated a novel mechanism whereby ΔNp63 efficiently sustains the expression of epidermal differentiation genes. We show that ΔNp63 interacts with Senataxin (SETX), an RNA/DNA helicase able to resolve the R-loop intermediates over the GC-rich termination sites of coding genes. Notably, we found that SETX and ΔNp63 co-regulate a subset of genes involved in the early step of the keratinocyte differentiation program. At the molecular level, SETX physically binds the p63 DNA binding motifs present in two early epidermal differentiation genes, Keratin 1 (KRT1) and ZNF750, facilitating R-loop removal over their 3’ ends and thus promoting efficient transcriptional termination and gene expression. Remarkably, SETX loss affects the activation of the proper epidermal differentiation program in vitro and impacts epidermal layer stratification in organotypic human skin. Furthermore, we found that SETX is mutated or downmodulated in SCC and SETX gene mutation is a negative prognostic factor for cutaneous SCC patient survival. Collectively, our results unveil SETX as a novel molecular player of skin homeostasis, potentially involved in hyperproliferative skin disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193205 | GEO | 2022/01/10

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The long non-coding NEAT1 is a DNp63 target gene able to modulate epidermal differentiation [RNA-seq]

Project description:The transcription factor ΔNp63, a master regulator of epithelial biology, is involved in regulating epithelial stem cell function and maintaining the integrity of stratified epithelial tissues such as the epidermis. To this end, ΔNp63 acts as transcriptional repressor or activator towards a distinct subset of protein-coding genes and microRNAs. However, how and whether ∆Np63 regulates long non-coding RNA (lncRNAs) expression is not known. Here, we identified the lncRNAs NEAT1 and MALAT1 as a bona fide ΔNp63 transcriptional targets. We found that in proliferating human keratinocytes ∆Np63 represses NEAT1 and MALAT1 expression by recruiting the histone deacetylates HDAC1/HDAC2 to the p63 DNA binding site located in the proximal promoter of NEAT1 and MALAT1 genomic loci. Upon induction of differentiation, ∆Np63 down-regulation is associated by a marked increase of NEAT1 RNA levels, resulting in an increased assembly of paraspeckles foci both in vitro and in human skin tissues. RNA-seq analysis associated with global DNA binding profile (ChIRP-seq) revealed that NEAT1 associates with the promoter of key epithelial transcription factors sustaining their expression during epidermal differentiation. These molecular events might explain the inability of NEAT1-depleted keratinocytes to undergo the correct epidermal differentiation program. Remarkably, NEAT1 expression is dysregulated in those skin pathologies characterized by aberrant keratinocytes differentiation such as ichthyosis and psoriasis, suggesting its potential involvement in the pathogenesis of skin disorders.

2023-05-17 | GSE205960 | GEO

The long non-coding NEAT1 is a DNp63 target gene able to modulate epidermal differentiation [ChIRP-seq]

2023-05-17 | GSE205959 | GEO

Deletion of Mediator (Med1) induces epidermal fate in dental epithelial stem cells

Project description:Cell fates are defined by specific transcriptional program. We developed a mouse model, in which transcriptional program for ectoderm cell fate is altered in tooth and skin. Previously, we showed that genomic deletion of one subunit of Mediator complex, Mediator 1 (Med1) in vivo regenerate ectopic hair in incisors by disrupting Notch mediated enamel epithelial differentiation. However, precise process and molecular mechanism to induce epidermal fate are not clear. Med1 deficient dental epithelial stem cells exerts transcriptional program for skin epithelia reminiscent of the pattern in the skin. Epidermal transcripts were first induced prior to hair genes during dental epithelial differentiation, resemble to the pattern of embryonic developmental process of the skin. Hair genes was specifically induced at the anagen stage synchronized with hair cycling in the skin. Epidermal program was also induced in cultured adult stem cells called dental epithelial stem cell (DESC) that is derived from micro-dissected Med1 KO cervical loop tissues that are essential for continuous regeneration of mouse incisors. Gene expression profiles for the primary DESC with colony forming capability revealed that Med1 deletion suppressed Tgfb signaling by reducing the expression of ligands (Tgfb1, Inhibin ba), receptors and their extracellular targets such as Ctgf. Med1 deletion also induced Tgfb regulated reprogramming transcription factor, Klf4 that also known to drive transcription for epidermal genes. TGFb signaling was also suppressed in Med1 null epidermis in skin, in which epidermal fate was induced in hair follicle keratinocytes. Med1 silencing blocked expression of TGFb1 and suppressed both basal and recombinant TGFb induced Smad2/3 mediated transcription of TGFb target genes in vitro. These results demonstrate that Med1 deletion enhances epidermal transcriptional program in adult stem cells through regulation of TGFb signaling.

2018-12-31 | GSE112884 | GEO

Ablation of coactivator Med1 switches the cell fate of dental epithelia to that generating hair [mixed stage]

Project description:Cell fate is defined by specific transcriptional program. Here, we provide evidence that the transcriptional coactivator, Mediator 1 (MED1), is critical in determining the cell fate of ectodermal epithelia. MED1 ablation disrupted enamel formation and generated hair adjacent to the incisors. Deletion of MED1 altered the differentiation of dental epithelia to one expressing epidermal and hair genes similar to the skin. The cellular switch from dental to epidermal/hair lineage was characterized by abnormalities in MED1 deficient dental epithelial stem cells residing in cervical loop. MED1 deficiency caused a failure of dental epithelial stem cells to commit to the dental stratum intermedium regulated by Notch signaling. Instead, MED1 deficient cells retained stem cell potentials expressing Sox2. These cells were eventually adopted an epidermal fate probably through calcium provided through capillary networks, which is originally utilized for enamel formation. Our results demonstrate that MED1 regulates Sox2/Notch1 regulated cell lineage determination in dental epithelia. Our study also shows a potential to regenerate hairs by using genetically engineered dental tissues or cells outside of the skin. n=3 WT and KO (each sample contain dissected dental tissues from 3 mice combined)

2013-09-23 | E-GEOD-50503 | biostudies-arrayexpress

Ablation of coactivator Med1 switches the cell fate of dental epithelia to that generating hair [maturation stage]

Project description:Cell fate is defined by specific transcriptional program. Here, we provide evidence that the transcriptional coactivator, Mediator 1 (MED1), is critical in determining the cell fate of ectodermal epithelia. MED1 ablation disrupted enamel formation and generated hair adjacent to the incisors. Deletion of MED1 altered the differentiation of dental epithelia to one expressing epidermal and hair genes similar to the skin. The cellular switch from dental to epidermal/hair lineage was characterized by abnormalities in MED1 deficient dental epithelial stem cells residing in cervical loop. MED1 deficiency caused a failure of dental epithelial stem cells to commit to the dental stratum intermedium regulated by Notch signaling. Instead, MED1 deficient cells retained stem cell potentials expressing Sox2. These cells were eventually adopted an epidermal fate probably through calcium provided through capillary networks, which is originally utilized for enamel formation. Our results demonstrate that MED1 regulates Sox2/Notch1 regulated cell lineage determination in dental epithelia. Our study also shows a potential to regenerate hairs by using genetically engineered dental tissues or cells outside of the skin. n=4 WT and KO (each group contains dissected dental tissues from 3 mice combined)

2013-09-23 | E-GEOD-50502 | biostudies-arrayexpress

Ablation of coactivator Med1 switches the cell fate of dental epithelia to that generating hair [CL stage]

2013-09-23 | E-GEOD-50501 | biostudies-arrayexpress

The ULK3 kinase is a key determinant of keratinocyte self-renewal and tumorigenesis targeting the arginine methylome

Project description:Epigenetic mechanisms oversee epidermal homeostasis and oncogenesis. The identification of kinases controlling these processes has direct therapeutic implications. We show that ULK3 is a nuclear kinase with elevated expression levels in squamous cell carcinomas (SCCs) arising in multiple body sites, including skin and Head/Neck. ULK3 loss by gene silencing or deletion reduces proliferation and clonogenicity of human keratinocytes and SCC-derived cells and affects transcription impinging on stem cell-related and metabolism programs. Mechanistically, ULK3 directly binds and regulates the activity of two histone arginine methyltransferases, PRMT1 and PRMT5 (PRMT1/5), with ULK3 loss compromising PRMT1/5 chromatin association to specific genes and overall methylation of histone H4, a shared target of these enzymes. These findings are of translational significance, as downmodulating ULK3 by RNA interference or locked antisense nucleic acids (LNAs) blunts the proliferation and tumorigenic potential of SCC cells and promotes differentiation in two orthotopic models of skin cancer.

2022-11-14 | MTBLS5155 | MetaboLights

ΔNp63 controls stemness and inflammation in the adult epidermis

Project description:The p63 transcription factor is critical for epidermis formation in embryonic development, but its role in the adult epidermis is barely investigated. Here we show that acute genetic ablation of ΔNp63, the main p63 isoform, in the adult epidermis disrupts keratinocyte proliferation and self-maintenance and, unexpectedly, triggers an inflammatory psoriasis-like condition. Mechanistically, single-cell RNA sequencing revealed down-regulation of the cell cycle genes, up-regulation of differentiation markers, and induction of several pro-inflammatory pathways in ΔNp63-ablated keratinocytes. Intriguingly, ΔNp63-ablated cells disappear three weeks post-ablation, at the expense of the remaining non-ablated cells. This was not associated with active cell death mechanisms, but rather with reduced stemness and self-maintenance capacity. Indeed, in vivo wound healing assay, a physiological readout of the epidermal stem cell function, was largely impaired in the ablated skin. We found that the Wnt signaling pathway (Wnt5a, Wnt10a, Fzd6, Fzd10) and Col17a1 are the likely ΔNp63 effectors responsible for keratinocyte proliferation and stemness, while AP1 factors are responsible for excessive differentiation, and Il-1a, Il-18, Il-24 and Il-36γ for the suppression of inflammation. These data implicate ΔNp63 as a critical node that coordinates balanced epidermal homeostasis and suppression of inflammation in the adult epidermis, upstream of known regulatory pathways.

2023-03-31 | GSE213528 | GEO

Epigenetic regulation of iASPP-p63 feedback loop in cutaneous squamous cell carcinoma

Project description:Keratinocyte skin cancer, comprising cutaneous squamous (cSCC) and basal cell carcinoma, is the most common malignancy in the UK. P53 is frequently mutated in cSCC. iASPP is a key inhibitor of p53 and NF-kB signalling pathways and has been documented as highly expressed in several types of human cancer. We have previously identified an autoregulatory feedback loop between iASPP and p63, which is critical in epidermal homeostasis. We hypothesised a potential role for dysregulation of this axis in the pathogenesis of keratinocyte malignancies. Immunostaining of 116 cSCC clinical samples revealed increased iASPP and ΔNp63 expression but also highlighted a significant alteration of iASPP cellular localisation, with consequent deregulation of its function. Expression patterns, functionality, gene and microRNA expression analysis were further investigated in 10 cSCC cell lines. Our data suggest that whilst direct effects of iASPP and p63 upon each other’s expression are maintained in cSCC, epigenetic dysregulation of the feedback loop occurs at the microRNA level by a novel mechanism controlling p63 expression. We demonstrate that this autoregulatory feedback loop controls cell migration in cSCC by blocking EMT and promoting proliferation, and provides future directions for clinical biomarker and therapeutic target discovery in cutaneous SCC.

2019-11-20 | GSE123189 | GEO

KGF effects on cutaneous SCC cells

Project description:Keratinocyte growth factor (KGF, fibroblast growth factor-7) is a fibroblast-derived mitogen, which stimulates proliferation of epithelial cells. The expression of KGF by dermal fibroblasts is induced following injury and it promotes wound repair. However, the role of KGF in cutaneous carcinogenesis and cancer progression is not known. We have examined the role of KGF in progression of squamous cell carcinoma (SCC) of the skin. Gene expression profiling was performed of three cutaneous SCC cell lines treated with KGF (10 ng/ml) for 24 h, comparable untreated cells and of normal unterated epidermal keratinocytes to explore KGF-responce in SCC cells. Three cutanous SCC cell lines (established from two primary and one metastatic tumors) were cultured to 70% confluency, serum starved (0% FCS) for 16 h and treated with rKGF (10 ng/ml) for 24 h. Comparable cell cultures were left untreated with rKGF. Normal epidermal keratinocytes from two individuals were cultured in specified keratinocyte culture medium to 70% confluency. All cell cultures were processed for RNA extraction and Affymetrix whole transcript microarray gene expression analysis. Thus, the samples included three untreated cutaeous SCC cell lines (n=3), the same three cell lines treated with rKGF (n=3) and untreated epidermal keratinocytes from two individuals (n=2). Normal keratinocytes served as reference samples to untreated skin SCC cells.

2012-05-01 | E-GEOD-34652 | biostudies-arrayexpress

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