Epidermal overexpression of ∆NLef1 leads to deregulation of epidermal stem cell fate
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PROVIDER: PRJNA484336 | ENA |
REPOSITORIES: ENA
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Project description:In adult K14ÎNLef1 mouse, the overexpression of âNLef1, a B-catenin dominat negative, in basal keratinocytes leads to the conversion of hair follicles into multilayered epithelial cysts and ectopic sebaceous gland. To uncover in vivo changes in gene expression associated to âNLef1 activity, we compared the expression profiles of unfractionated keratinocytes in wild type and K14ÎNLef1 transgenic mice. Cells were collected from 9.5 week old mice, when the hair follicle are in the resting (telogen) phase of the hair growth cycle. At this stage the âNLef1 phenotype is not yet evident enabling us to detect early molecular events. We compared the expression profiles of unfractionated keratinocytes in wild type and K14ÎNLef1 transgenic 9.5 week old mice. Three biological replicates for each cell population were analyzed.
2017-05-16 | E-GEOD-62603 | biostudies-arrayexpress
Project description:In adult K14ΔNLef1 mouse, the overexpression of ∆NLef1, a B-catenin dominat negative, in basal keratinocytes leads to the conversion of hair follicles into multilayered epithelial cysts and ectopic sebaceous gland. To uncover in vivo changes in gene expression associated to ∆NLef1 activity, we compared the expression profiles of unfractionated keratinocytes in wild type and K14ΔNLef1 transgenic mice. Cells were collected from 9.5 week old mice, when the hair follicle are in the resting (telogen) phase of the hair growth cycle. At this stage the ∆NLef1 phenotype is not yet evident enabling us to detect early molecular events.
2017-05-16 | GSE62603 | GEO
Project description:In adult K14ΔNLef1 mouse, the overexpression of ∆NLef1, a B-catenin dominat negative, in basal keratinocytes leads to the conversion of hair follicles into multilayered epithelial cysts and ectopic sebaceous gland. To uncover in vivo changes in gene expression associated to ΔNLef1 activity, we compared the expression profiles of basal keratinocytes (Itga6+) and bulge stem cells (cd34+/itga6+) in wild type and K14ΔNLef1 transgenic mice. Cells were collected from 9.5 week old mice, when the hair follicle are in the resting (telogen) phase of the hair growth cycle. At this stage the ΔNLef1 phenotype is not yet evident enabling us to detect early molecular events.
2019-03-08 | GSE118073 | GEO
Project description:Epidermal overexpression of ∆NLef1 leads to deregulation of epidermal stem cell fate.
| PRJNA264532 | ENA
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:Gata6 network regulates epidermal junctional zone cell fate.
| PRJNA264527 | ENA
Project description:This is a Phase 1, single-dose, open-label, dose-escalation study. The study will be conducted in three parts (i.e. regimens) in an outpatient setting as follows:
* Regimen A: FATE-NK100 as a monotherapy in subjects with advanced solid tumor malignancies.
* Regimen B: FATE-NK100 in combination with trastuzumab in subjects with human epidermal growth factor receptor 2 positive (HER2+) advanced breast cancer, HER2+ advanced gastric cancer or other advanced HER2+ solid tumors.
* Regimen C: FATE-NK100 in combination with cetuximab in subjects with advanced colorectal cancer (CRC) or head and neck squamous cell cancer (HNSCC), or other epidermal growth factor receptor 1 positive (EGFR1+) advanced solid tumors.
| 2257146 | ecrin-mdr-crc
Project description:The vitamin D receptor with its ligand 1,25 dihydroxy vitamin D3 (1,25D3) regulates epidermal stem cell fate, such that VDR removal from Krt14 expressing keratinocytes delays re-epithelialization of epidermis after wound injury in mice. In this study we deleted Vdr from Lrig1 expressing stem cells in the isthmus of the hair follicle then used lineage tracing to evaluate the impact on re-epithelialization following injury. We showed that Vdr deletion from these cells prevents their migration to and regeneration of the interfollicular epidermis without impairing their ability to repopulate the sebaceous gland. To pursue the molecular basis for these effects of VDR, we performed genome wide transcriptional analysis of keratinocytes from Vdr cKO and control littermate mice. Ingenuity Pathway analysis (IPA) pointed us to the TP53 family including p63 as a partner with VDR, a transcriptional factor that is essential for proliferation and differentiation of epidermal keratinocytes. Epigenetic studies on epidermal keratinocytes derived from interfollicular epidermis showed that VDR is colocalized with p63 within the specific regulatory region of MED1 containing super-enhancers of epidermal fate driven transcription factor genes such as Fos and Jun. Gene ontology analysis further implicated that Vdr and p63 associated genomic regions regulate genes involving stem cell fate and epidermal differentiation. To demonstrate the functional interaction between VDR and p63, we evaluated the response to 1,25(OH)2D3 of keratinocytes lacking p63 and noted a reduction in epidermal cell fate determining transcription factors such as Fos, Jun. We conclude that VDR is required for the epidermal stem cell fate orientation towards interfollicular epidermis following wounding. We propose that this role of VDR involves cross-talk with the epidermal master regulator p63 through super-enhancer mediated epigenetic dynamics.
2023-07-22 | GSE230578 | GEO
Project description:Progenitor cells at the basal layer of skin epidermis play an essential role in maintaining tissue homeostasis and enhancing wound repair in skin. The proliferation, differentiation, and cell death of epidermal progenitor cells have to be delicately regulated, as deregulation of this process can lead to many skin diseases, including skin cancers. However, the underlying molecular mechanisms involved in skin homeostasis remain poorly defined. In this study, with quantitative proteomics approach, we identified an important interaction between KDF1 (Keratinocyte Differentiation Factor 1) and IKKα (IκB kinase α) in differentiating skin keratinocytes. Ablation of either KDF1 or IKKα in mice leads to similar but striking abnormalities in skin development, particularly in skin epidermal differentiation. With biochemical and mouse genetics approach, we further demonstrate that the interaction of IKKα and KDF1 is essential for epidermal differentiation. To probe deeper into the mechanisms, we find that KDF1 associates with a deubiquitinating protease, USP7 (Ubiquitin Specific Peptidase 7), and KDF1 can regulate skin differentiation through deubiquitination and stabilization of IKKα. Taken together, our study unravels an important molecular mechanism underlying skin tissue homeostasis and epidermal differentiation.
2020-05-13 | PXD015673 | Pride
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