biostudies-literatureFerris ENIA NIH HHSNIMH NIH HHSNHGRI NIH HHSNLM NIH HHS494-500https://www.ebi.ac.uk/biostudies/studies/S-EPMC12434793biostudies-literatureUnknown389(6759)Extreme metabolic adaptations can elucidate genetic programs that govern mammalian metabolism. Here, we used convergent evolutionary changes in hibernating lineages to define conserved cis-regulatory elements (CREs) and metabolic programs. We characterized mouse hypothalamus gene expression and chromatin dynamics across fed, fasted, and refed states and then used comparative genomics of hibernating versus nonhibernating lineages to identify cis elements with convergent changes in hibernators. Multi-omics approaches pinpointed CREs, hub genes, regulatory programs, and cell types underlying lineage divergence. Hibernators accumulated loss-of-function effects for CREs regulating hypothalamic responses, and the refeeding period after fasting served as a key phase for molecular processes with cScience (New York, N.Y.)Genomic convergence in hibernating mammals elucidates the genetics of metabolic regulation in the hypothalamus.PMC12434793RF1 AG077201R01 AG064013T15 LM007124R01 MH109577T32 HG008962Rodriguez ACTraenkner DFerris EMaldonado-Catala PJGonzalez Murcia JDStacher Horndli CSteinwand SGregg CfalseGenomic convergence in hibernating mammals elucidates the genetics of metabolic regulation in the hypothalamus.Extreme metabolic adaptations can elucidate genetic programs that govern mammalian metabolism. Here, we used convergent evolutionary changes in hibernating lineages to define conserved cis-regulatory elements (CREs) and metabolic programs. We characterized mouse hypothalamus gene expression and chromatin dynamics across fed, fasted, and refed states and then used comparative genomics of hibernating versus nonhibernating lineages to identify cis elements with convergent changes in hibernators. Multi-omics approaches pinpointed CREs, hub genes, regulatory programs, and cell types underlying lineage divergence. Hibernators accumulated loss-of-function effects for CREs regulating hypothalamic responses, and the refeeding period after fasting served as a key phase for molecular processes with c2025-01-01T00:00:00Z2025 Jul2026-06-03T07:59:58.98Z2026-04-26T03:12:02.202ZS-EPMC124347934074333310.1126/science.adp4025