Abstract
The regulatory elements controlling gene expression during acute inflammation are not fully elucidated. Here we report the identification of a set of NF-κB-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-α, we identify extensive (~30%) conserved orthologous binding of NF-κB to accessible, as well as nucleosome-occluded chromatin. Regions with the highest NF-κB occupancy pre-stimulation show dramatic increases in NF-κB binding and chromatin accessibility post-stimulation. These ‘pre-bound’ regions are typically conserved (~56%), contain multiple NF-κB 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-κB regions within the super-enhancer associated with the chemokine-encoding CCL2 gene and elsewhere supports the functional relevance of these elements.
Highlights
The regulatory elements controlling gene expression during acute inflammation are not fully elucidated
These experiments were performed in primary human aortic endothelial cells (ECs) (HAECs), mouse aortic ECs (MAECs), and bovine aortic ECs (BAECs) under basal and TNFα-stimulated conditions (Fig. 1a and Supplementary Dataset 1)
Since we found RELA to be consistently enriched in the nucleus from 15 min up to 45 min after TNFα treatment (Supplementary Fig. 1a), we processed samples 45 min post-treatment to facilitate the observation of immediate epigenomic and transcriptional changes induced by RELA
Summary
The regulatory elements controlling gene expression during acute inflammation are not fully elucidated. Regions with the highest NF-κB occupancy pre-stimulation show dramatic increases in NF-κB binding and chromatin accessibility post-stimulation These ‘prebound’ regions are typically conserved (~56%), contain multiple NF-κB motifs, are utilized by diverse cell types, and overlap rare non-coding mutations and common genetic variation associated with both inflammatory and cardiovascular phenotypes. In response to cytokines such as tumor necrosis factor alpha (TNFα), pro-inflammatory gene regulation is mediated through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a conserved transcription factor (TF). Induction of IκBα terminates the response and results in the shuttling of inactive NF-κB back into the cytoplasm, resetting it for subsequent activation[12] These oscillations of NFκB signaling from latency to response followed by resolution are conserved from Drosophila to human[13], making NF-κB a paradigmatic rapid response factor[2]
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