Innate immune responses rely on rapid and precise gene regulation mediated by accessibility of regulatory regions to transcription factors (TFs). In natural killer (NK) cells and other innate lymphoid cells, competent enhancers are primed during lineage acquisition, and formation of de novo enhancers characterizes the acquisition of innate memory in activated NK cells and macrophages. Here, we investigated how primed and de novo enhancers coordinate to facilitate high-magnitude gene induction during acute activation. Epigenomic and transcriptomic analyses of regions near highly induced genes (HIGs) in NK cells both in vitro and in a model of Toxoplasma gondii infection revealed de novo chromatin accessibility and enhancer remodeling controlled by signal-regulated TFs STATs. Acute NK cell activation redeployed the lineage-determining TF T-bet to de novo enhancers, independent of DNA-sequence-specific motif recognition. Thus, acute stimulation reshapes enhancer function through the combinatorial usage and repurposing of both lineage-determining and signal-regulated TFs to ensure an effective response.

先天免疫反应依赖于由调控区域对转录因子 (TF) 的可及性介导的快速和精确的基因调控。在自然杀伤 (NK) 细胞和其他先天淋巴细胞中，有能力的增强子在谱系获取过程中被启动，从头增强子的形成表征了激活的 NK 细胞和巨噬细胞中先天记忆的获取。在这里，我们研究了启动和从头增强子如何协调以促进急性激活期间的高幅度基因诱导。体外和弓形虫感染模型中 NK 细胞中高度诱导基因 (HIG) 附近区域的表观基因组学和转录组学分析揭示了从头染色质可及性和增强子重塑由信号调节的 TFs STATs 控制。急性 NK 细胞激活将谱系决定 TF T-bet 重新部署到从头增强子，独立于 DNA 序列特异性基序识别。因此，急性刺激通过组合使用和重新利用谱系确定和信号调节 TF 来重塑增强子功能，以确保有效反应。