Acute hormonal signaling-induced 3D chromatin loop reorganization controls adipocyte thermogenesis [ChIP-Seq mouse, H3K27ac, H3K4me3, H2AZ]

β3-adrenergic receptor (β3-AR) hormonal signaling is imperative for adaptative thermogenesis, facilitating heat generation during cold exposure. This study explores how β3-AR signaling regulates thermogenic gene activation by altering the three-dimensional (3D) genome organization. Our findings reveal a rapid 3D genome reorganization in brown adipocytes following 4 hours of β3-AR stimulation, highlighted by high-resolution Micro-C analysis. This reorganization involves substantial dynamic changes in chromatin loops, coupled with activation of genes involved in thermogenesis. Mechanistically, β3-AR signaling promotes the p18Hamlet/SRCAP complex assembly, catalyzing the chromatin incorporation of the histone variant H2A.Z. H2A.Z incorporation enhances chromatin accessibility at loop anchors, facilitating loop formation. Disruption of H2A.Z impairs loop dynamics and thermogenic function of brown adipocytes, with implications for both mice and humans. Notably, human homologous loop anchors are associated with obesity-related genetic variants. This study underscores the critical role of 3D genome architecture in thermogenic regulation, offering new dimensions into obesity’s molecular underpinnings.