Genomic convergence in hibernating mammals elucidates the genetics of metabolic regulation in the hypothalamus

• 成果类型: Article
• 署名作者: Ferris, Elliott; Gonzalez Murcia, Josue D.; Rodriguez, Adriana Cristina; Steinwand, Susan; Stacher Horndli, Cornelia; Traenkner, Dimitri; Maldonado-Catala, Pablo J.; 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
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12579
• DOI: 10.1126/science.adp4025
• 发表日期: 2025-07-31
• 页码: 494-500
• 关键词: accelerated evolution; neuronal plasticity; cis-elements; expression; tau; heat-shock-protein-70; activation; protein

摘要

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 convergent evolutionary changes. This work provides a genetic framework for harnessing hibernator adaptations to understand human metabolic control.