Dynamicity of Topoisomerase 1 binding at super-enhancers regulates TLR-responsive gene expression program in macrophages

Toll-like receptor (TLR) activation elicits an effective innate immune response by inducing the expression of primary and secondary response genes (PRGs and SRGs). Topoisomerase 1 (TOP1) has emerged as a critical regulator of innate immune responses; however, its mechanism of action remains largely unclear. Here, we demonstrate that ectopic expression of TOP1 is sufficient to program TLR-response in naïve macrophages and its catalytic activity is essential for inducible gene expression. TOP1 preferentially localizes to super-enhancers and TLR activation results in rapid redistribution of TOP1 from resting-state super-enhancers to stimulus-gained super-enhancers, leading to a transcriptional switch. Notably, TOP1 facilitates the recruitment of BRG1 to stimulus-gained super-enhancers. The cooperation between TOP1 and BRG1 enhances the chromatin accessibility at super-enhancers to preferentially regulate the expression of SRGs. These findings establish TOP1 as an epigenomic regulator that links chromatin remodeling at active super-enhancers with inducible gene expression in response to pathogenic stimuli.