Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis

By D. Malhotra, Elodie Portales-Casamar, Anju Singh, Siddhartha Srivastava, David J. Arenillas, Christine Happel, C. Shyr, N. Wakabayashi, T. Kensler, Wyeth W. Wasserman and 1 more. Nucleic Acids Research, 2010

783 citations recorded by the source corpus.

The Nrf2 (nuclear factor E2 p45-related factor 2) transcription factor responds to diverse oxidative and electrophilic environmental stresses by circumventing repression by Keap1, translocating to the nucleus, and activating cytoprotective genes. Nrf2 responses provide protection against chemical carcinogenesis, chronic inflammation, neurodegeneration, emphysema, asthma and sepsis in murine models. Nrf2 regulates the expression of a plethora of genes that detoxify oxidants and electrophiles and repair or remove damaged macromolecules, such as through proteasomal processing. However, many direct targets of Nrf2 remain undefined. Here, mouse embryonic fibroblasts (MEF) with either constitutive nuclear accumulation (Keap1−/−) or depletion (Nrf2−/−) of Nrf2 were utilized to perform chromatin-immunoprecipitation with parallel sequencing (ChIP-Seq) and global transcription profiling. This unique Nrf2 ChIP-Seq dataset is highly enriched for Nrf2-binding motifs. Integrating ChIP-Seq and microarray analyses, we identified 645 basal and 654 inducible direct targets of Nrf2, with 244 genes at the intersection. Modulated pathways in stress response and cell proliferation distinguish the inducible and basal programs. Results were confirmed in an in vivo stress model of cigarette smoke-exposed mice. This study reveals global circuitry of the Nrf2 stress response emphasizing Nrf2 as a central node in cell survival response.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/2995a59062eddcda0f18e0cb90d2ebe1f3ac90a1

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Citations in the corpus

Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions (2022, background): “As Nrf2 is phosphorylated through the protein kinase C pathway, it becomes uncoupled from Keap1, leading to enhanced expression of various antiinflammatory proteins, antioxidant enzymes, and growth factors.(111,112) In ischemic stroke, oxidative stress caused by elevated ROS levels induces Nrf2 accu”
Transcriptional Regulation by Nrf2 (2017, methodology): “Transcriptional profiles of Nfe2l2 knockout mice showed that Nrf2 is not just involved in inducible gene expression in response to an activating agent but also involved in the constitutive expression of several antioxidant and detoxification genes in the absence of external stresses (13, 100, 164).”
The cytoprotective role of the Keap1–Nrf2 pathway (2011, background): “ChIP-PCR and qRT-PCR assays found the cell cycle inhibitors p21 and p15 to be direct targets of induced Nrf2-mediated transcription (Malhotra et al. 2010).”
Role of nrf2 in oxidative stress and toxicity. (2013, background): “In addition, Nrf2 regulates proteasomal protein degradation (83), cell proliferation (84), and metabolic reprogramming (85), which are not discussed in this review.”
Mitochondrial reactive oxygen species and cancer (2014, background): “increase expression of antioxidants including GPXs and glutathione synthesis and utilization genes [26,27].”
TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO (2012, background): “Genes that are regulated by Nrf1 (Mt1) (Ohtsuji et al., 2008) or Nrf2 (others) (Malhotra et al., 2010; Wu et al., 2011) were assayed along with the FoxO target G6Pase (Mihaylova et al., 2011).”
NRF2, a Transcription Factor for Stress Response and Beyond (2020, background): “Gene transcription profiles revealed that not all genes in the vicinity of bound NRF2 are transcriptionally regulated by NRF2 binding [49,50].”
Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. (2012, background): “These genes, except for Me1, were also listed as direct target genes of Nrf2 in an earlier ChIP-seq analysis with anti-Nrf2 antibody using MEFs (Malhotra et al., 2010).”
Antioxidants Accelerate Lung Cancer Progression in Mice (2014, background): “Consistent with this notion, experimental studies show that oncogenes such as K-RAS and B-RAF promote tumor growth by stimulating NRF2-mediated transcription of endogenous antioxidant genes (13, 14).”