title: Bcl-6 and NF-kappaB cistromes mediate opposing regulation of the innate immune response.
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.
authors.affiliation: Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
authors.forename: Grant D
authors.initials: GD
authors.lastname: Barish
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.forename: Malith
authors.initials: M
authors.lastname: Karunasiri
authors.forename: Corinne B
authors.initials: CB
authors.lastname: Ocampo
authors.forename: Jesse
authors.initials: J
authors.lastname: Dixon
authors.forename: Chris
authors.initials: C
authors.lastname: Benner
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Dent
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Tangirala
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000276:immunology*; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation / Q000276:immunology*; D007113:Immunity, Innate / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051560:Proto-Oncogene Proteins c-bcl-6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4