Year: 2010
Type: preprint
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.
Source: Genes & Development
DOI: 10.1101/gad.1998010
Language: English
Topic: NF-κB Signaling Pathways
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: bronze
Funders: Howard Hughes Medical Institute, March of Dimes Foundation, Samuel Waxman Cancer Research Foundation, National Institutes of Health, Weill Cornell Medical College, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, David Geffen School of Medicine, University of California, Los Angeles
Awards: Adiponectin Actions on the Monocyte to Reduce Atherosclerosis, Spatial Regulation of Developmental Gene Expression, Hormonal Regulation of Mammalian Gene Expression, Repressor-PPAR Interactions in Inflammation and Atherosclerosis, G57110349, Role of Immune Mechanisms in Athersclerosis and Inflammation, Nuclear Receptors and Coregulators in Health and Disease, Diabetes Research Center (DRC)
OpenAlex ID: W2134397552