title: Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis.
abstract: 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.
authors.affiliation: Department of Environmental Health Sciences Department, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Deepti
authors.initials: D
authors.lastname: Malhotra
authors.forename: Elodie
authors.initials: E
authors.lastname: Portales-Casamar
authors.forename: Anju
authors.initials: A
authors.lastname: Singh
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Srivastava
authors.forename: David
authors.initials: D
authors.lastname: Arenillas
authors.forename: Christine
authors.initials: C
authors.lastname: Happel
authors.forename: Casper
authors.initials: C
authors.lastname: Shyr
authors.forename: Nobunao
authors.initials: N
authors.lastname: Wakabayashi
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.forename: Wyeth W
authors.initials: WW
authors.lastname: Wasserman
authors.forename: Shyam
authors.initials: S
authors.lastname: Biswal
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001665:Binding Sites; D002453:Cell Cycle; D049109:Cell Proliferation; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D050436:Regulatory Elements, Transcriptional; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic; D015262:Xenobiotics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D015262:Xenobiotics
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