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

• 成果类型: Article
• 署名作者: Steinwand, Susan; Horndli, Cornelia Stacher; Ferris, Elliott; Emery, Jared; Gonzalez Murcia, Josue D.; Rodriguez, Adriana Cristina; Spotswood, Riley J.; Chaix, Amandine; Thomas, Alun; Davey, Crystal; Gregg, Christopher
• 署名单位: Utah System of Higher Education; University of Utah; Utah System of Higher Education; University of Utah; Utah System of Higher Education; University of Utah; Utah System of Higher Education; University of Utah; Utah System of Higher Education; University of Utah; Utah System of Higher Education; University of Utah
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9311
• DOI: 10.1126/science.adp4701
• 发表日期: 2025-07-31
• 页码: 501-507
• 关键词: fto gene; enhancer; variant; interrogation; physiology; responses; circuits; clusters; torpor; mass

摘要

Cis-regulatory elements (CREs) drive phenotypic diversity, yet how CREs are causally linked to function remains largely unclear. Our study elucidates functions for conserved cis elements 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 cis elements forming regulatory contacts with neighboring genes. Deletions of individual cis elements 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.