Bcl-6 and NF-κB cistromes mediate opposing regulation of the innate immune response (original) (raw)

  1. Ruth T. Yu1,
  2. Malith Karunasiri1,
  3. Corinne B. Ocampo1,
  4. Jesse Dixon1,
  5. Chris Benner2,
  6. Alexander L. Dent3,
  7. Rajendra K. Tangirala4 and
  8. Ronald M. Evans1,5
  9. 1Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California 92037, USA;
  10. 2Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA;
  11. 3Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA;
  12. 4Division of Endocrinology, Diabetes, and Hypertension, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA

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.

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