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

Deepti Malhotra, Elodie Portales-Casamar, Anju Singh, Siddhartha Srivastava, David Arenillas, Christine Happel, Casper Shyr, Nobunao Wakabayashi, Thomas W. Kensler, Wyeth W. Wasserman, Shyam Biswal

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbergkq212
Pages (from-to)5718-5734
Number of pages17
JournalNucleic acids research
Volume38
Issue number17
DOIs
StatePublished - May 11 2010

ASJC Scopus subject areas

  • Genetics

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    Malhotra, D., Portales-Casamar, E., Singh, A., Srivastava, S., Arenillas, D., Happel, C., Shyr, C., Wakabayashi, N., Kensler, T. W., Wasserman, W. W., & Biswal, S. (2010). Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through chip-seq profiling and network analysis. Nucleic acids research, 38(17), 5718-5734. [gkq212]. https://doi.org/10.1093/nar/gkq212