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Project description:The Aryl Hydrocarbon Receptor (AHR) is an environmental sensor and an indispensable regulator of epithelial homeostasis. To investigate AHR-mediated gene regulation, we performed a comprehensive transcriptomic and epigenomic analysis using human primary epidermal keratinocytes. Our results showed that AHR activation led to the induction of canonical transcription factors involved in epidermal differentiation as an early response, i.e. Transcription Factor AP-2α (TFAP2A), while epidermal differentiation-related genes, such as filaggrin and keratins, were activated as late responsive genes. The identified AHR-TFAP2A axis and its role in keratinocyte terminal differentiation was confirmed through AHR and TFAP2A knockout using CRISPR/Cas9. Our findings demonstrate that AHR regulates epidermal differentiation through the transient activation of specific transcription factors, such as TFAP2A, in response to environmental cues. The herein identified AHR-TFAP2A axis provides a promising target for the treatment of diseases related to skin barrier dysfunction.
2023-09-08 | GSE226046 | GEO
Project description:The Aryl Hydrocarbon Receptor (AHR) is an environmental sensor and an indispensable regulator of epithelial homeostasis. To investigate AHR-mediated gene regulation, we performed a comprehensive transcriptomic and epigenomic analysis using human primary epidermal keratinocytes. Our results showed that AHR activation led to the induction of canonical transcription factors involved in epidermal differentiation as an early response, i.e. Transcription Factor AP-2α (TFAP2A), while epidermal differentiation-related genes, such as filaggrin and keratins, were activated as late responsive genes. The identified AHR-TFAP2A axis and its role in keratinocyte terminal differentiation was confirmed through AHR and TFAP2A knockout using CRISPR/Cas9. Our findings demonstrate that AHR regulates epidermal differentiation through the transient activation of specific transcription factors, such as TFAP2A, in response to environmental cues. The herein identified AHR-TFAP2A axis provides a promising target for the treatment of diseases related to skin barrier dysfunction.
2023-09-08 | GSE226045 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2014-11-11 | GSE52954 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2017-05-16 | E-GEOD-62608 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-07-05 | GSE205746 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-05-01 | E-GEOD-59827 | biostudies-arrayexpress
Project description:Environmental conditions can have a major impact on developmental progression in animals. For example, when C. elegans larvae encounter harsh conditions they can reversibly halt the passage of developmental time by forming a long-lived dauer larva at the end of the second larval stage. Here, we show that the period homolog lin-42, known to control developmental time, also acts as a component of a switch that mediates dauer entry. Loss of lin-42 function renders animals hypersensitive to dauer formation under stressful conditions, whereas misexpression of lin-42 in the pre-dauer stage inhibits dauer formation, indicating that lin-42 acts as a negative regulator of this life history decision. These phenotypes place LIN-42 in opposition to the ligand-free form of the nuclear receptor DAF-12, which indirectly senses environmental conditions and helps to integrate external cues into developmental decisions. Mutations that impair DAF-12 ligand binding are exquisitely sensitive to the absence of lin-42, whereas overexpression of LIN-42 can suppress the dauer constitutive phenotype of a ligand-insensitive daf-12 mutant, suggesting that LIN-42 and DAF-12 are intimate partners in controlling the decision to become a dauer larva. The functional outputs of Period family proteins and nuclear receptors also converge in other organisms, suggesting that the relationship between lin-42 and daf-12 represents an ancient genetic framework for responding to environmental stimuli.
| S-EPMC2947761 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-07-31 | E-GEOD-68730 | biostudies-arrayexpress
Project description:The nuclear hormone receptor PPAR?/? is integral to efficient wound re-epithelialization and implicated in epidermal maturation. However, the mechanism underlying the latter process of epidermal differentiation remains unclear. We showed that ligand-activated PPAR?/? indirectly stimulated keratinocyte differentiation, requiring de novo gene transcription and protein translation. Using organotypic skin cultures constructed from PPAR?/?- and angiopoietin-like 4 (ANGPTL4)-knockdown human keratinocytes, we showed that the expression of ANGPTL4, a PPAR?/? target gene, is essential for the receptor mediated epidermal differentiation. The pro-differentiation effect of PPAR?/? agonist GW501516 was also abolished when keratinocytes were co-treated with PPAR?/? antagonist GSK0660 and similarly in organotypic skin culture incubated with blocking ANGPTL4 monoclonal antibody targeted against the C-terminal fibrinogen-like domain. Our focused real-time PCR gene expression analysis comparing the skin biopsies from wildtype and ANGPTL4-knockout mice confirmed a consistent down-regulation of numerous genes involved in epidermal differentiation and proliferation in the ANGPTL4-knockout skin. We further showed that the deficiency of ANGPTL4 in human keratinocytes and mice skin have diminished expression of various protein kinase C isotypes and phosphorylated transcriptional factor activator protein-1, which are well-established for their roles in keratinocyte differentiation. Chromatin immunoprecipitation confirmed that ANGPTL4 stimulated the activation and binding of JUNB and c-JUN to the promoter region of human involucrin and transglutaminase type 1 genes, respectively. Taken together, we showed that PPAR?/? regulates epidermal maturation via ANGPTL4-mediated signalling pathway.
| S-EPMC3178651 | biostudies-literature
Project description:Activation of the transcription factor, AHR, in normal human epidermal keratinocytes increased AHR binding in the gene regions of the glucose transporter, SLC2A1, and the glycolytic enzyme, ENO1. This increased chromatin binding corresponded with AHR-dependent decreases in levels of SLC2A1 and ENO1 mRNA, protein, and activities. Studies of the ENO1 promoter showed activation of the AHR decreases the transcription of ENO1. Glycolysis was lowered by activation of the AHR as measured by decreases in glucose uptake and the production of pyruvate and lactate. Levels of ATP were also decreased. Downregulation of glucose metabolism, either by activation of the AHR, inhibition of glycolysis, inhibition of glucose transport, or inhibition of enolase, increased SIRT1 protein levels in normal human epidermal keratinocytes and the immortalized keratinocyte cell line, N/TERT-1. This increase in SIRT1 was abrogated by the addition of exogenous pyruvate. Moreover, keratinocyte differentiation in response to downregulation of glycolysis, either by activation of the AHR, inhibition of glucose transport, or inhibition of enolase, was dependent on SIRT1. These results indicate that regulation of glycolysis controls keratinocyte differentiation, and that activation of the AHR, by lowering the expression of SLC2A1 and ENO1, can determine this fate.
| S-EPMC6431567 | biostudies-literature