Steinwand Susan, Hörndli Cornelia Stacher, Ferris Elliott, Emery Jared, Gonzalez Murcia Josue D, Rodriguez Adriana Cristina, Spotswood Riley J, Chaix Amandine, Thomas Alun, Davey Crystal, Gregg Christopher
Department of Neurobiology, University of Utah, Salt Lake City, UT, USA.
Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.
Science. 2025 Jul 31;389(6759):501-507. doi: 10.1126/science.adp4701.
Cisregulatory 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 () 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 , , and 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.
顺式调控元件（CREs）驱动表型多样性，但CREs如何与功能产生因果联系在很大程度上仍不清楚。我们的研究阐明了与哺乳动物冬眠和代谢灵活性进化相关的保守顺式元件的功能。基因组分析揭示了冬眠动物中富含趋同变化的拓扑相关结构域（TADs），包括（）位点。在这个TAD中，我们发现了代谢反应的遗传回路以及与相邻基因形成调控接触的冬眠相关顺式元件。小鼠中单个顺式元件的缺失以不同方式改变了、和的表达，重塑了下游基因表达程序，并以不同方式影响代谢、蛰伏、肥胖发生和觅食。我们的研究结果表明，冬眠动物的趋同进化如何确定代谢控制的功能性遗传机制，单个CRE中编码了多种效应。
