Regulation of transcriptional signal integration and memory by inflammation-induced chromosome conformation [ATAC-Seq]

3-dimensional (3D) genome conformation is central to gene expression regulation, yet our understanding of how rapid transcriptional responses, transcriptional memory, and integration of different environmental signals are orchestrated in the 3D genome is limited. Here, we study various aspects of the inflammatory response in macrophages using transcriptomic, epigenomic, and genome conformation mapping technologies, including high-resolution Micro-Capture C. We report that interleukine-4 (IL-4) stably rewires the 3D genome conformation of macrophages and juxtaposes endotoxin-, interferon-gamma-, and dexamethasone-activated enhancers to cognate gene promoters to support enhanced gene expression. IL-4-driven conformational change is indispensable for the integration of IL-4- and endotoxin-induced enhanced and synergistic transcriptional responses, provides short-term transcriptional memory, and can occur in the absence of IL-4-induced epigenetic and transcriptional changes. Our work reveals that IL-4-driven 3D genome conformation is required to shape macrophage plasticity to subsequent immunological responses, integrate distinct inflammatory signals, and provides memory.