A conserved hormonal signalling–H2A.Z axis rapidly reorganizes 3D chromatin interactions in adipocyte thermogenesis

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Abstract
Three-dimensional genome organization underlies gene regulation, yet how acute hormonal signalling reshapes chromatin structure to control metabolism remains unclear. β3-adrenergic receptor (β3-AR) hormonal signalling drives adipocyte thermogenesis. Here, we show three-dimensional genome maps of mouse and primary human brown adipocytes during thermogenesis using Micro-C. We find that β3-AR signalling rapidly reorganizes chromatin loops within 4 h, with dynamically gained loops coupled to thermogenic gene activation in both species. Mechanistically, β3-AR stimulation promotes histone variant H2A.Z deposition to enhance chromatin accessibility at loop anchors, facilitating the recruitment of bridging factor MED1. Loss of H2A.Z compromises loop formation and thermogenic gene activation across species. Brown fat-specific H2A.Z deficiency in mice impairs thermogenic activity and glucose tolerance. Integration with genome-wide association studies links H2A.Z-occupied loops to genetic variants associated with obesity and related metabolic disorders. Together, our findings uncover a cross-species conserved β3-AR signalling–H2A.Z axis that rapidly reorganizes chromatin interactions in adipocyte thermogenesis, providing mechanistic and translational insights into metabolic regulation.

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