Bcl-6 and NF-κB cistromes mediate opposing regulation of the innate immune response

Grant D. Barish, Ruth T. Yu, Malith Karunasiri, Corinne B. Ocampo, Jesse Dixon, Chris Benner, Alexander L. Dent, Rajendra K. Tangirala, Ronald M. Evans

Research output: Contribution to journalArticle

167 Scopus citations

Abstract

In the macrophage, toll-like receptors (TLRs) are key sensors that trigger signaling cascades to activate inflammatory programs via the NF-κB gene network. However, the genomic network targeted by TLR/NF-κB activation and the molecular basis by which it is restrained to terminate activation and re-establish quiescence is poorly understood. Here, using chromatin immunoprecipitation sequencing (ChIP-seq), we define the NF-κB cistrome, which is comprised of 31,070 cis-acting binding sites responsive to lipopolysaccharide (LPS)-induced signaling. In addition, we demonstrate that the transcriptional repressor B-cell lymphoma 6 (Bcl-6) regulates nearly a third of the Tlr4-regulated transcriptome, and that 90% of the Bcl-6 cistrome is collapsed following Tlr4 activation. Bcl-6-deficient macrophages are acutely hypersensitive to LPS and, using comparative ChIP-seq analyses, we found that the Bcl-6 and NF-κB cistromes intersect, within nucleosomal distance, at nearly half of Bcl-6-binding sites in stimulated macrophages to promote opposing epigenetic modifications of the local chromatin. These results reveal a genomic strategy for controlling the innate immune response in which repressive and inductive cistromes establish a dynamic balance between macrophage quiescence and activation via epigenetically marked cis-regulatory elements.

Original languageEnglish (US)
Pages (from-to)2760-2765
Number of pages6
JournalGenes and Development
Volume24
Issue number24
DOIs
StatePublished - Dec 15 2010

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Keywords

  • Bcl-6
  • ChIP-seq
  • Inflammation, cistrome
  • Macrophage
  • Nf-κB

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Barish, G. D., Yu, R. T., Karunasiri, M., Ocampo, C. B., Dixon, J., Benner, C., Dent, A. L., Tangirala, R. K., & Evans, R. M. (2010). Bcl-6 and NF-κB cistromes mediate opposing regulation of the innate immune response. Genes and Development, 24(24), 2760-2765. https://doi.org/10.1101/gad.1998010