RNA-seq analysis of NRF2 silenced human skin fibroblasts
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ABSTRACT:
PROVIDER: PRJNA767694 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16134839.fastq.gz | Fastqsanger.gz | |||
| SRR16134840.fastq.gz | Fastqsanger.gz | |||
| SRR16134841.fastq.gz | Fastqsanger.gz | |||
| SRR16134842.fastq.gz | Fastqsanger.gz | |||
| SRR16134843.fastq.gz | Fastqsanger.gz |
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Project description:This RNA-seq analysis was the beginning of our study, to have a first global unbiased approach to analyze the effect of NRF2 silencing on the mRNA profile of human skin fibroblasts. We demonstrated that besides NRF2 conventional antioxidant and metabolic target genes, tissue skeleton and especially matrisome genes were affected by NRF2 silencing. We further confirmed that NRF2 silencing some collagen genes, impacting collagen fibrillogenesis.
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Project description:The NRF2 transcription factor is a key regulator of the cellular antioxidant response, and pharmacological NRF2 activation is a promising strategy for the prevention of age-related diseases. Here we show, however, that genetic activation of Nrf2 in skin fibroblasts leads to the production of a matrisome, which is similar to aged skin and characterized by reduced synthesis and deposition of selected matrix proteins, including the major skin collagens. Mechanistically, the production of an aging matrisome results from Nrf2-mediated overexpression of microRNAs (miRs), which directly suppress collagen expression independently of myofibroblast differentiation. This is functionally important, as Nrf2 activation in fibroblasts caused structural abnormalities of the dermal ECM and increased the susceptibility to skin tearing, similar to aged skin. Activation of endogenous NRF2 was observed in human skin from elderly individuals in vitro and in vivo. These data implicate a key role for activated NRF2 in controlling age-related molecular and biomechanical skin alterations.
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Project description:Differentially regulated miRNAs in skin fibroblasts with constitutively active Nrf2
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Project description:The Nrf2 transcription factor is a key player in the cellular stress response, which regulates the expression of important antioxidant enzymes and other cytoprotective proteins. We recently generated a novel transgenic mouse model to determine the function of Nrf2 in the skin. These mice revealed interesting phenotypic abnormalities, including hyperkeratosis and acanthosis. To gain insight into the underlying molecular mechanisms, we wanted to identify genes, which are differentially expressed in the skin of wild-type and mutant mice before the onset of phenotypic abnormalities. RNA from whole skin of 3 single P2.5 K5cre-caNrf2 (tg/tg) and 3 single P2.5 K5cre-wt (tg/wt=control) mice were used
2012-02-01 | E-GEOD-35160 | biostudies-arrayexpress
Project description:Nrf2 is a key regulator of the cellular antioxidant defense system, and pharmacological Nrf2 activation is a promising strategy for cancer prevention. Here we discovered a novel role of Nrf2 as a regulator of the matrisome. Activation of Nrf2 in fibroblasts induced early onset of cellular senescence. Mechanistically, this resulted from Nrf2-mediated transcription of matrix and matrix-remodeling genes. Fibroblasts with activated Nrf2 deposited a senescence-promoting matrix, with plasminogen-activator inhibitor being the key inducer of the senescence program. In vivo, this promoted keratinocyte proliferation and re-epithelialization during wound healing, but also skin tumorigenesis. Analysis of the gene expression profile of fibroblasts with activated Nrf2 and published data sets revealed that Nrf2 activates genes characteristic for cancer-associated fibroblasts. These data identify Nrf2 as a key player in the control of the cancer-associated fibroblast phenotype and highlight the need for careful use of Nrf2-activating pharmaceuticals.
2018-08-30 | GSE106097 | GEO
Project description:Long wavelength Ultraviolet (UVA-1) radiation causes oxidative stress that leads to the formation of noxious substances within the skin. As a defensive mechanism skin cells produce detoxifying enzymes and antioxidants when they detect modified molecules. We have recently shown that UVA-1 irradiation oxidizes the abundant membrane phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC), which then induced the synthesis of the stress response protein heme oxygenase 1 (HO-1) in dermal fibroblasts. Here we examined the effects of UVA-1 and (UV-) oxidized phospholipids on the global gene expression in human dermal fibroblasts. We identified a cluster of genes that were co-induced by UVA-1-oxidized PAPC and UVA-1 radiation. The cluster included HO-1, glutamate-cysteine ligase modifier subunit (GCLM), aldo-keto reductases-1-C1 and -C2 (AKR1C1, AKR1C2), and interleukin 8 (IL8). These genes are members of the cellular stress response system termed âantioxidant responseâ or âPhase II detoxificationâ. Accordingly, the regulatory regions of all these genes contain binding sites for NF-E2-related factor 2 (Nrf2), a major regulator of the antioxidant response. Both UVA-1 irradiation and treatment with oxidized lipids led to increased nuclear accumulation of Nrf2. Silencing expression of Nrf2 using siRNA or using cells and tissue from Nrf2-deficient mice, we show that the induction of the co-regulated genes was suppressed. Expression of other canonical UVA-1-induced genes, including cyclooxygenase 2 (Cox2) and interleukin 6 (IL6) was unaltered in the absence of Nrf2. Together, our data show that UVA-1-mediated lipid oxidation induces induction of antioxidant response genes, which is dependent on the redox-regulated transcription factor Nrf2. To activate Nrf2 is a major strategy for novel antioxidant drugs, the skin photo-adaptation (SPA) inducers. Our finding that specific uv-oxidized lipids act similar sheds a new (ultraviolet) light on the usually detrimental âimageâ of UV generated lipid mediators. Experiment Overall Design: we profiled global mRNA expression levels in human dermal fibroblasts that had been treated with either UVA-1 or oxidized lipids. To investigate the effect of oxidized phospholipids on gene regulation, we used two preparations, which differed in their degree of oxidation; the minimally oxidized UV-PAPC resulting from UVA-1 irradiation of PAPC, and air-oxidized PAPC (OxPAPC), which represents the full spectrum of oxidation products (Gruber 07) (Reis et al., 2005). We irradiated dermal fibroblasts with UVA-1 (40J/cm²) or treated them with UV-PAPC, OxPAPC or native PAPC (100µg/ml each). We analyzed global gene expression four hours after stimulation with gene arrays (Affymetrix U133A Plus 2.0 Gene Chips).
2009-11-10 | E-GEOD-13606 | biostudies-arrayexpress
Project description:Nrf2-regulated mRNAs are known; however, no Nrf2-regulated miRs have been identified miR microarray analysis from total RNA samples was performed to test which miRs are regulated by Nrf2 Total RNA from skin of mice with constitutively active Nrf2 (CMV-caNrf2), dominant-negative Nrf2 (dnNrf2), and correcponding control littermates (K5Cre(wt) for CMV-caNrf2 and wt for dnNrf2)
2015-01-01 | E-GEOD-52454 | biostudies-arrayexpress
Project description:The Nrf2 transcription factor is a key player in the cellular stress response, which regulates the expression of important antioxidant enzymes and other cytoprotective proteins. We recently generated a novel transgenic mouse model to determine the function of Nrf2 in the skin. These mice revealed interesting phenotypic abnormalities, including hyperkeratosis and acanthosis. To gain insight into the underlying molecular mechanisms, we wanted to identify genes, which are differentially expressed in the skin of wild-type and mutant mice before the onset of phenotypic abnormalities.
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Project description:Spatial localisation of human skin fibroblasts
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Project description:Long wavelength Ultraviolet (UVA-1) radiation causes oxidative stress that leads to the formation of noxious substances within the skin. As a defensive mechanism skin cells produce detoxifying enzymes and antioxidants when they detect modified molecules. We have recently shown that UVA-1 irradiation oxidizes the abundant membrane phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC), which then induced the synthesis of the stress response protein heme oxygenase 1 (HO-1) in dermal fibroblasts. Here we examined the effects of UVA-1 and (UV-) oxidized phospholipids on the global gene expression in human dermal fibroblasts. We identified a cluster of genes that were co-induced by UVA-1-oxidized PAPC and UVA-1 radiation. The cluster included HO-1, glutamate-cysteine ligase modifier subunit (GCLM), aldo-keto reductases-1-C1 and -C2 (AKR1C1, AKR1C2), and interleukin 8 (IL8). These genes are members of the cellular stress response system termed “antioxidant response” or “Phase II detoxification”. Accordingly, the regulatory regions of all these genes contain binding sites for NF-E2-related factor 2 (Nrf2), a major regulator of the antioxidant response. Both UVA-1 irradiation and treatment with oxidized lipids led to increased nuclear accumulation of Nrf2. Silencing expression of Nrf2 using siRNA or using cells and tissue from Nrf2-deficient mice, we show that the induction of the co-regulated genes was suppressed. Expression of other canonical UVA-1-induced genes, including cyclooxygenase 2 (Cox2) and interleukin 6 (IL6) was unaltered in the absence of Nrf2. Together, our data show that UVA-1-mediated lipid oxidation induces induction of antioxidant response genes, which is dependent on the redox-regulated transcription factor Nrf2. To activate Nrf2 is a major strategy for novel antioxidant drugs, the skin photo-adaptation (SPA) inducers. Our finding that specific uv-oxidized lipids act similar sheds a new (ultraviolet) light on the usually detrimental “image” of UV generated lipid mediators.
2009-10-22 | GSE13606 | GEO