Hospital for Sick Children, Genetics and Genome Biology, Toronto, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
Nat Commun. 2021 Jan 25;12(1):567. doi: 10.1038/s41467-020-20765-1.
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.
调控急性炎症期间基因表达的元件尚未完全阐明。在这里，我们报告了一组 NF-κB 结合元件和共同的染色质景观的鉴定，这些元件是哺乳动物细胞类型和物种急性炎症反应的基础。使用用促炎细胞因子肿瘤坏死因子-α处理的原代血管内皮细胞（人/鼠/牛），我们发现 NF-κB 广泛（30%）保守地结合到可及的以及核小体封闭的染色质上。在刺激前 NF-κB 结合最高的区域在刺激后 NF-κB 结合和染色质可及性显著增加。这些“预先结合”的区域通常是保守的（56%），包含多个 NF-κB 基序，被多种细胞类型利用，并且与炎症和心血管表型相关的罕见非编码突变和常见遗传变异重叠。在与趋化因子 CCL2 基因相关的超级增强子内以及其他地方保守的、“预先结合”的 NF-κB 区域的遗传缺失支持这些元件的功能相关性。
