Acute hormonal signaling-induced 3D chromatin loop reorganization controls adipocyte thermogenesis [PRO-seq mouse]

Recent molecular advancements have revolutionized our understanding of the role of three-dimensional (3D) genome organization in gene regulation. Yet, the impact of acute hormonal signaling on reshaping genome structure and its consequences for metabolic processes remain largely unexplored. β3-adrenergic receptor (β3-AR) hormonal signaling is imperative for brown adipose tissue (BAT) thermogenesis. Here, we demonstrate that β3-AR signaling induces rapid reorganization of fine-scale genome architecture in murine and human brown adipocytes within four hours. High-resolution Micro-C profiling reveals dynamic chromatin loop formation associated with activation of thermogenic genes. Mechanistically, β3-AR signaling promotes p18Hamlet/SRCAP complex assembly, catalyzing incorporation of the histone variant H2A.Z into nucleosomes. ATAC-sequencing reveals that H2A.Z enhances chromatin accessibility at loop anchors, supporting loop formation by facilitating the recruitment of looping factors such as the Mediator complex. Disruption of H2A.Z compromises dynamic chromatin looping and transcriptional activation of thermogenic genes in both species. Mice with BAT-specific H2A.Z deficiency exhibit reduced thermogenic activity and impaired glucose tolerance. Revisiting genome-wide association study analysis reveals that H2A.Z-occupied loops are linked to genetic variants associated with obesity and its related metabolic disorders. Together, these findings highlight the rapid adaptability of 3D genome organization to acute β3-AR signaling and its critical role in brown adipocyte thermoregulation.