Transgenic expression of Nrf2 in the mouse
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE202298 | GEO | 2022/05/09
REPOSITORIES: GEO
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Project description:Background: Although modern advances in the treatment of heart disease have reduced mortality rates, long-term medical management is often associated with a progressive loss of function that manifests as heart failure. Nuclear factor, erythroid 2 like 2 (Nfe2l2, a.k.a. Nrf2) is a transcriptional regulator that provides the ischemic heart with transient cytoprotection following acute myocardial insult; however, its sustained activation paradoxically causes reductive stress, an emerging pathological phenomenon characterized by excessive antioxidant function and proteotoxic remodeling. Yet, the molecular mechanism by which chronic reductive stress produces heart failure remains elusive. Methods: Cardiac-specific constitutively active Nrf2 transgenic (caNrf2-Tg) mice expressing the transgene at low (TgL) and high (TgH) levels were employed in integrative mRNA and small RNA (miRNA) sequencing. Results and Conclusion: Here, we reveal several Nrf2 dose-responsive miRNA loci harboring putative upstream antioxidant response elements (AREs). Intriguingly, Nrf2-mediated miRNA responses were distinctly enriched for post-transcriptional regulation of cardiac-specific mRNAs. Altogether, these data reveal Nrf2 as a potent regulator of cardiac miRNA expression and provide novel candidates for future mechanistic investigation into the relationship between myocardial redox status and pathophysiology.
2020-04-01 | GSE120088 | GEO
Project description:Background: Although modern advances in the treatment of heart disease have reduced mortality rates, long-term medical management is often associated with a progressive loss of function that manifests as heart failure. Nuclear factor, erythroid 2 like 2 (Nfe2l2, a.k.a. Nrf2) is a transcriptional regulator that provides the ischemic heart with transient cytoprotection following acute myocardial insult; however, its sustained activation paradoxically causes reductive stress, an emerging pathological phenomenon characterized by excessive antioxidant function and proteotoxic remodeling. Yet, the molecular mechanism by which chronic reductive stress produces heart failure remains elusive. Methods: Cardiac-specific constitutively active Nrf2 transgenic (caNrf2-Tg) mice expressing the transgene at low (TgL) and high (TgH) levels were employed in integrative mRNA and small RNA (miRNA) sequencing. Results and Conclusion: Here, we reveal several Nrf2 dose-responsive miRNA loci harboring putative upstream antioxidant response elements (AREs). Intriguingly, Nrf2-mediated miRNA responses were distinctly enriched for post-transcriptional regulation of cardiac-specific mRNAs. Altogether, these data reveal Nrf2 as a potent regulator of cardiac miRNA expression and provide novel candidates for future mechanistic investigation into the relationship between myocardial redox status and pathophysiology.
2020-04-01 | GSE120087 | GEO
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:Nuclear factor erythroid 2-related factor 2 (NFE2L2, Nrf2) is an oxidant responsive transcription factor known to induce phase 2 detoxifying and antioxidant genes to protect cells from oxidative stress. Cigarette smoke, with its large oxidant content, is a major stressor to the small airway epithelium, the cells of which are vulnerable to oxidant damage and consequent malignant transformation. In this study, we assessed the role of cigarette smoke in activation of Nrf2 in the human small airway epithelium in vivo. Fiberoptic bronchoscopy was used to sample a pure population of small airway epithelium in 38 healthy nonsmokers and 45 healthy smokers, and gene expression was assessed using Affymetrix HG-U133 Plus 2.0 microarrays. Compared to that of healthy nonsmokers, Nrf2 protein was significantly activated in the small airway epithelium of healthy normal smokers and localized in the nucleus (p<0.05). Of the human homologs of 201 known murine Nrf2-mediated genes, 13 highly smoking-responsive genes were identified (p<10-4, all comparisons smokers to nonsmokers). Using a “Nrf2-index” to quantify the extent of expression in the small airway epithelium of these 13 known Nrf2 genes, variability in the level of expression was observed among the 45 healthy smokers, but the variability was coordinately modulated among the 13 genes, an observation confirmed by TaqMan quantitative PCR. This variability in the coordinate level of expression of the 13 Nrf2-mediated genes was independent of the smoking history. Based on these observations, the “Nrf2 index” was used to evaluate whether other genes modulated by smoking in the small airway epithelium were also coordinately up- or down- modulated among the 45 healthy smokers. Two genes, pirin (PIR) and UDP glucuronosyltransferase 1 family polypeptide A4 (UGT1A4), not previously known to be modulated by Nrf2 were identified as being coordinately modulated among the 45 smokers. Both genes contain several functional antioxidant response elements in the promoter region. Using an electrophoretic mobility shift assay, these antioxidant response elements in the promoters of PIR and UGT1A4 responded in vitro to activated Nrf2. These observations are consistent with the concept that Nrf2 plays an important role in regulating cellular defenses against smoking in the highly vulnerable small airway epithelium cell population, and that there is variability among the population in the relative Nrf2 responsiveness to a similar oxidant burden. Affymetrix arrays were used to assess gene expression data in small airway epithelium obtained by fiberoptic bronchoscopy of 38 healthy non-smokers and 45 healthy smokers
2009-07-13 | E-GEOD-11952 | biostudies-arrayexpress
Project description:Due to the limited expression of several antioxidant enzymes, β-cells are highly vulnerable to high ROS levels, which can lead to the reduction of functional β-cell mass. During early postnatal ages, both human and rodent β-cells go through a burst of proliferation that quickly declines with age. Here we discovered that the expression of the master antioxidant regulator, Nrf2, is increased during this postnatal burst of β-cell proliferation in humans. Additionally, data from β-cell specific Nrf2 deletion in mice demonstrated that Nrf2 is required for β-cell proliferation, β-cell survival, β-cell identity and β-cell mass expansion at early stages of life. Daily administration of antioxidant NAC to newborn mice showed that Nrf2 mechanism of action strongly relies on maintaining normal redox balance. Interestingly, RNAseq of islets isolated from β-cell specific Nrf2 deleted mice suggests that Nrf2 regulates neonatal β-cell proliferation by promoting mitochondrial ATP synthesis. Our study highlights Nrf2 as an essential transcription factor for maintaining redox balance as well as mitochondrial biogenesis and function to support neonatal β-cell growth and for maintaining functional β-cell mass in adulthood under metabolic stress.
2023-12-19 | GSE242718 | GEO
Project description:ACTL6A has been identified as a transcriptional regulator and driving pathways that are of specific benefit to the malignant elements within the tumor. Here, we aimed to find genes that are regulated by ACTL6A by CUT&Tag. BRG1 is the catalytic subunit of the SWI/SNF chromatin-remodeling complex. Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2, NRF2) is a transcription factor that governs the antioxidant pathway. IgG was used as a control.
2023-04-20 | GSE216350 | GEO
Project description:Nrf2 is a transcription factor that binds to antioxidant response elements of the regulatory region of a number of antioxidant genes. A mutation in the Nrf2 gene increases susceptibility to hyperoxic lung injury. This project examines expression differences between wild type and Nrf2 knock out mice with the hope of providing insight to the downstream effector genes regulated by Nrf2.
2007-12-14 | E-GEOD-495 | biostudies-arrayexpress
Project description:Cellular oxidative and electrophilic stress triggers a protective response in mammals regulated by NRF2 (nuclear factor (erythroid-derived) 2-like; NFE2L2) binding to DNA-regulatory sequences near stress responsive genes. Studies using Nrf2-deficient mice suggest that hundreds of genes may be regulated by NRF2. To identify human NRF2-regulated genes, we conducted ChIP-sequencing experiments in lymphoid cells treated with the dietary isothiocyanate, sulforaphane (SFN) and carried out follow-up biological experiments on candidates. We found 242 high-confidence, NRF2-bound genomic regions and 96% of these regions contained NRF2-regulatory sequence motifs. The majority of binding sites were near potential novel members of the NRF2 pathway. Validation of selected candidate genes using parallel ChIP techniques and in NRF2-silenced cell lines indicated that the expression of about two thirds of the candidates are likely to be directly NRF2-dependent including retinoid X receptor alpha (RXRA). NRF2 regulation of RXRAhas implications for response to retinoid treatments and adipogenesis. In mouse 3T3-L1 cells SFN treatment affected Rxra expression early in adipogenesis and knockdown of Nrf2 delayed Rxra expression, both leading to impaired adipogenesis. ChIP-Seq analysis of NRF2 binding sites in human lymphoblastoid cells treated with sulforaphane or vehicle
2012-06-18 | E-GEOD-37589 | biostudies-arrayexpress
Project description:NFE2L2/NRF2 is a transcription factor and master regulator of the cellular antioxidant response. Aberrantly high NRF2-dependent transcription is recurrent in human cancer, resulting in increased cellular fitness, chemo-radiation resistance, metabolic reprogramming and immune evasion. NRF2 protein levels and activity is governed primarily by the KEAP1/CUL3 ubiquitin ligase and subsequent proteasomal degradation. To what extent parallel signaling pathways and protein classes impact NRF2 activity remains to be fully explored. Also, because NRF2-directed therapies remain in the discovery and early development stages, continued identification and validation of NRF2 regulators is of potential clinical value. Here we used a gain-of-function genetic screen of the kinome to identify druggable activators and inhibitors of NRF2 signaling. We found that the understudied Brain Selective Kinase 1 and 2 (BRSK1/2) proteins suppress NRF2-dependent transcription and NRF2 protein levels in a kinase-dependent fashion. Integrative phospho-proteomic screens, RNAseq profiling and follow-up validation studies revealed BRSK1/2-driven activation of AMPK and suppression of MTOR signaling. BRSK2 over-expression suppressed global protein synthesis and decreased ribosome-RNA associations, which results in decreased NRF2 protein levels. Overall, our data establish the BRSK1 and BRSK2 kinases as negative regulators of NRF2 via the AMPK/MTOR signaling axis. Strategies which exploit these relationships may prove useful for therapeutically targeting NRF2 in cancer.
2020-06-24 | PXD015884 | Pride
Project description:Transcriptional profiling of BL/6 mice harboring a mutant Kras allele, with or without knockouts of Stk11 and/or Keap1, or with expression of an Nfe2l2 transgene, Nrf2Tg. In lung adenocarcinoma (LUAD), stabilization of the transcription factor NRF2 through genomic alterations in KEAP1 and NFE2L2 occurs in roughly a quarter of patients, often in the context of STK11 tumor suppressor loss. In this study, we demonstrate that NRF2 activation in the context of concurrent KRAS mutation and STK11 loss promotes aggressive LUAD tumor behavior in both human and mouse preclinical models. This phenotype is associated with metabolic rewiring and rescue by NRF2 of redox stress, high in STK11 null tumors. Applying a novel, pan-lung cancer, diagnostic NRF2 activation gene expression signature that is independent of frequently co-occurring mutations, we dissect the independent contributions of the three most frequent genetic events in human LUAD (NRF2 activation, STK11 loss and KRAS mutations) on patient prognosis and clinical responses in a dataset of second-line LUAD patients treated with immunotherapy or chemotherapy (OAK trial). Our findings underscore that both individual effects and epistatic relationships among oncogenic and tumor suppressor pathways influence tumor biology, immune contexture and patient clinical outcomes. Our work also highlights the value of lung cancer disease sub-classification based on genetic and expression profiling as part of patient clinical management.
2020-01-31 | GSE133714 | GEO