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ABSTRACT:
PROVIDER: PRJNA1172466 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Studies on the mechanisms underlying Angiopoietin-like 4-induced epidermal stem cell proliferation
| PRJNA1188169 | ENA
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
Project description:The de novo DNA methyltransferase Dnmt3a is mutated in human acute myeloid leukemia, and suppresses tumorigenesis in murine models of leukemia and lung cancer. Conversely, deregulation of the other de novo DNA methyltransferase, Dnmt3b, predominantly promotes tumorigenesis. However, the molecular mechanisms underlying the roles of Dnmt3a and Dnmt3b in cancer remain poorly understood. Using conditional knockout mice, here we show that Dnmt3a -- but not Dnmt3b -- strongly protects epidermal stem cells from carcinogen-induced tumor initiation, without affecting the progression of benign lesions to aggressive carcinomas. Only upon combined deletion of Dnmt3a and Dnmt3b, squamous cell carcinomas acquired a more aggressive fate and even became metastatic, indicating that Dnmt3b is tumor-suppressive, rather than pro-tumorigenic, in epidermal neoplasia. Mechanistically, Dnmt3a promotes the expression of epidermal differentiation genes by interacting with their enhancers, and inhibits the expression of lipid metabolism and cell proliferation genes by directly methylating their promoters. Altogether, we demonstrate that Dnmt3a, but not Dnmt3b, is critical for suppressing epidermal tumor initiation, while both enzymes prevent tumor progression.
2017-06-13 | GSE92421 | GEO
Project description:Cell fates are defined by specific transcriptional program. Previously, we developed a unique stem cell regeneration mouse model, in which transcriptional program for ectoderm organs such as tooth and skin is switched. Genomic deletion of one subunit of Mediator complex, Med1, resulted in defective enamel regeneration, in which dental stem cells were inhibited from undergoing transcriptional program for dental fate. In stead, they exerted skin program for both hair and epidermis, and post-natally regenerate ectopic hairs in the incisors. Here, we report that Med1 also modulates epidermal and hair cell fates in the skin. Med1 ablation further enhanced epidermal and sebocyte fates, and accelerated injury induced epidermal regeneration. However, it blunted hair fate resulting in hair loss in the skin. Ablation of Med1 increased the number of isthmus stem cells and epidermal stem cells, which regenerate epidermis during cutaneous wound healing process. Med1 deficiency also constitutively activated these stem cells and increased their proliferation. Microarray profiling indicated that Med1 deletion causes activation of β-catenin and suppression of TGFβ signaling. Med1 deficiency induced the expression of β-catenin target genes to control cell fate and proliferation. It also decreased TGFβ expression in interfollicular epidermis. Med1 deficiency increased the proliferation and migration of epidermal cells, and induced nuclear translocation of β-catenin, and decreased TGFβ1 expression in vitro. Our finding together with previous observations demonstrated that Med1 governs ectoderm cell fate in both tooth and skin. Med1 ablation blunts hair fate but induces epidermal and sebocyte cell fates to accelerated injury induced epidermal regeneration in the skin. Accelerated regeneration is derived from constitutive activation of epidermal stem cells accompanied with increased proliferation and migration of their progeny by balancing of β-catenin induced growth promoting and TGFβ mediated growth inhibitory activities in the skin.
2017-06-30 | GSE89967 | GEO
Project description:Successful ex vivo expansion of hematopoietic stem cells (HSCs) would greatly benefit the treatment of disease and the understanding of critical questions of stem cell biology. Microarray studies showed that the HSC supportive mouse fetal liver CD3+ cells specifically expressed angiopoietin-like 2 (Angptl2) and angiopoietin-like 3 (Angptl3). When highly enriched HSCs were cultured in the presence of Angptl2 or Angptl3 together with saturating levels of other growth factors for 10 days, a 24 or 30 fold net expansion of long-term HSCs was observed by reconstitution analysis. The coiled-coil domain of Angptl2 mediated the effects of Angptl2 on HSC expansion. Furthermore, angiopoietin-like 5, angiopoietin-like 7, and microfibril-associated glycoprotein 4 also supported expansion of HSCs in culture. Experiment Overall Design: Cultured 3 different cell types Experiment Overall Design: -> Total RNA isolation -> dscDNA -> Biotinylated cRNA -> hybridization to Affymetrix U74Bv2 and U74Cv2 mouse chips
2008-06-12 | E-GEOD-3609 | biostudies-arrayexpress
Project description:Sivakumar2011 - EGF Receptor Signaling Pathway
EGFR belongs to the human epidermal receptor (HER) family of receptor tyrosine kinases, which consists of four closely related receptors (EGFR (HER1, erbB1), HER2 (neu, erbB2), HER3 (erbB3), and HER4 (erbB4)) that mediate cellular signaling pathways involved in growth and proliferation in response to the binding of a variety of growth factor ligands. There are currently six known endogenous ligands for EGFR: EGF, transforming growth factor- (TGF-), amphiregulin, betacellulin, heparin-binding EGF (HB-EGF), and epiregulin.Upon ligand binding, the EGFR forms homo- or heterodimeric complexes (usually with HER2), which leads to activation of the receptor tyrosine kinase, via autophosphorylation.
References:
The EGF receptor family--multiple roles in proliferation, differentiation, and neoplasia with an emphasis on HER4.
An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors.
EGF receptor signaling: putting a new spin on eye development.
Epidermal growth factor receptor: a promising target in solid tumours.
This model is described in the article:
A systems biology approach to model neural stem cell regulation by notch, shh, wnt, and EGF signaling pathways.
Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S.
Omics: a Journal of Integrative Biology. 2011; 15(10):729-737
Abstract:
The Notch, Sonic Hedgehog (Shh), Wnt, and EGF pathways have long been known to influence cell fate specification in the developing nervous system. Here we attempted to evaluate the contemporary knowledge about neural stem cell differentiation promoted by various drug-based regulations through a systems biology approach. Our model showed the phenomenon of DAPT-mediated antagonism of Enhancer of split [E(spl)] genes and enhancement of Shh target genes by a SAG agonist that were effectively demonstrated computationally and were consistent with experimental studies. However, in the case of model simulation of Wnt and EGF pathways, the model network did not supply any concurrent results with experimental data despite the fact that drugs were added at the appropriate positions. This paves insight into the potential of crosstalks between pathways considered in our study. Therefore, we manually developed a map of signaling crosstalk, which included the species connected by representatives from Notch, Shh, Wnt, and EGF pathways and highlighted the regulation of a single target gene, Hes-1, based on drug-induced simulations. These simulations provided results that matched with experimental studies. Therefore, these signaling crosstalk models complement as a tool toward the discovery of novel regulatory processes involved in neural stem cell maintenance, proliferation, and differentiation during mammalian central nervous system development. To our knowledge, this is the first report of a simple crosstalk map that highlights the differential regulation of neural stem cell differentiation and underscores the flow of positive and negative regulatory signals modulated by drugs.
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2024-09-02 | BIOMD0000000394 | BioModels
Project description:Successful ex vivo expansion of hematopoietic stem cells (HSCs) would greatly benefit the treatment of disease and the understanding of critical questions of stem cell biology. Microarray studies showed that the HSC supportive mouse fetal liver CD3+ cells specifically expressed angiopoietin-like 2 (Angptl2) and angiopoietin-like 3 (Angptl3). When highly enriched HSCs were cultured in the presence of Angptl2 or Angptl3 together with saturating levels of other growth factors for 10 days, a 24 or 30 fold net expansion of long-term HSCs was observed by reconstitution analysis. The coiled-coil domain of Angptl2 mediated the effects of Angptl2 on HSC expansion. Furthermore, angiopoietin-like 5, angiopoietin-like 7, and microfibril-associated glycoprotein 4 also supported expansion of HSCs in culture. Keywords: Cell type comparison
2006-03-01 | GSE3609 | GEO
Project description:Millions suffer from skin diseases. Functional epidermal stem cells are needed in skin therapy or drug screening in vitro. We obtained functional epidermal stem cells with intact stemness and cell junctions by treating them with wnt3a. Moreover, epidermal stem cell-derived exosomes were useful in epidermal development. Finally, functional epidermal 3D organoids with polarity were cultured using wnt3a and the supernatant derived from epidermal stem cells and fresh medium in a 1:1 ratio. These results provide novel directions for the improvement of skin organoids and their potential in clinical application.
2020-07-14 | PXD020351 |
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
Project description:The vitamin D receptor (VDR) regulates cell proliferation and differentiation including epidermal keratinocytes by modulating transcription of its target genes. We are investigating the role of VDR in epidermal stem cells and their progenies in the regeneration process of epidermis and hair in the skin. VDR null mice are utilized in which VDR is specifically deleted in keratin 14 (K14) expressing keratinocytes by Cre-lox strategy. The impact of VDR deletion was evaluated by comparison of VDR null mice with no cre littermate control mice. The VDR was abundantly expressed in potential epidermal stem cells including basal cells in interfollicular epidermis (IFE), and in CD34 expressing bulge keratinocytes in hair follicles. Gene expression profiles and subsequent pathway analysis of stem cell enriched keratinocyte populations revealed that the VDR deletion significantly suppressed β-catenin signaling as well as VDR signaling. The role of VDR in epidermal stem cells was studied during hair follicle cycling and wound healing processes. The epidermal stem cells were not appropriately stimulated by hair depilation, and did not reinitiate anagen in the hair follicles resulting in a failure of hair regrowth. In addition, the stem cells were not fully activated after full thickness wounds were generated in VDR null skin under a low calcium diet to suppress compensation pathways. Cell proliferation was not fully induced in potential stem cells located in both IFE and hair follicles near the wounding edges, and re-epithelialization rate was delayed in VDR null skin. Gene expression profiling of the wounded skin (3 days after injury) indicated that β-catenin signaling was not fully induced in VDR null skin comparable to that observed in β-catenin null mice. The β-catenin target genes including Axin2 and cell cycle regulators involved in epidermal stem cell function were not induced in the edges of the wound of VDR null skin. These results demonstrated that VDR plays an essential role in hair cycling and wound healing processes through regulation of β-catenin signaling in epidermal stem cells and their progenies. n=3 CON and KO (each sample contain RNA isolated from wounded or nonwounded skins excised from 3 mice)
2015-07-31 | E-GEOD-68727 | biostudies-arrayexpress