Conserved regulatory logic at accessible and inaccessible chromatin during the acute inflammatory response in mammals.

ABSTRACT: The regulatory elements controlling gene expression during acute inflammation are not fully elucidated. Here we report the identification of a set of NF-?B-bound elements and common chromatin landscapes underlying the acute inflammatory response across cell-types and mammalian species. Using primary vascular endothelial cells (human/mouse/bovine) treated with the pro-inflammatory cytokine, Tumor Necrosis Factor-?, we identify extensive (~30%) conserved orthologous binding of NF-?B to accessible, as well as nucleosome-occluded chromatin. Regions with the highest NF-?B occupancy pre-stimulation show dramatic increases in NF-?B binding and chromatin accessibility post-stimulation. These 'pre-bound' regions are typically conserved (~56%), contain multiple NF-?B motifs, are utilized by diverse cell types, and overlap rare non-coding mutations and common genetic variation associated with both inflammatory and cardiovascular phenotypes. Genetic ablation of conserved, 'pre-bound' NF-?B regions within the super-enhancer associated with the chemokine-encoding CCL2 gene and elsewhere supports the functional relevance of these elements.

SUBMITTER: Alizada A 

PROVIDER: S-EPMC7835376 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature