Regulation of immune signal integration and memory by inflammation-induced chromosome conformation

Abstract

Significance Innate immune cells integrate inflammatory cues and retain transcriptional memory, a phenomenon previously attributed mainly to one-dimensional epigenetic mechanisms. We show that inflammatory cytokine exposure remodels the three-dimensional (3D) genome of macrophages by establishing stable chromatin loops that persist after stimulus withdrawal. These “memory loops” connect signal-responsive enhancers with promoters, enabling enhanced and integrated transcriptional responses to subsequent, mechanistically distinct stimuli, even in the absence of canonical epigenetic or transcriptional changes. Using base-pair resolution chromosome conformation mapping and causal CRISPR perturbations, we demonstrate that 3D genome architecture is functionally required for innate immune memory. Our findings uncover a previously unrecognized layer of immune regulation and redefine how inflammatory memory is encoded in chromatin.