Conserved noncoding cis elements associated with hibernation modulate metabolic and behavioral adaptations in mice

Cis-regulatory elements (CREs) drive phenotypic diversity, yet how CREs are causally linked to function remains largely unclear. Our study elucidates functions for conserved ciselements associated with the evolution of mammalian hibernation and metabolic flexibility. Genomic analyses revealed topologically associated domains (TADs) enriched for convergent changes in hibernators, including the Fat Mass & Obesity (Fto) locus. In this TAD, we uncovered genetic circuits for metabolic responses and hibernation-linked ciselements forming regulatory contacts with neighboring genes. Deletions of individual ciselements in mice differentially altered Fto, Irx3, and Irx5 expression, reshaping downstream gene expression programs and affecting metabolism, torpor, obesogenesis, and foraging in distinct ways. Our findings show how convergent evolution in hibernators pinpoints functional genetic mechanisms of metabolic control, with multiple effects encoded in single CREs.