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

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-07-31 DOI:10.1126/science.adp4701

Susan Steinwand, Cornelia Stacher Hörndli, Elliott Ferris, Jared Emery, Josue D. Gonzalez Murcia, Adriana Cristina Rodriguez, Riley J. Spotswood, Amandine Chaix, Alun Thomas, Crystal Davey, Christopher Gregg

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Abstract

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.

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与小鼠冬眠调节代谢和行为适应相关的保守非编码顺式元件

顺式调控元件（cre）驱动表型多样性，但cre与功能之间的因果关系仍不清楚。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。基因组分析显示，冬眠动物的拓扑相关结构域（TADs）富集于收敛性变化，包括脂肪质量（Fat Mass）；肥胖（Fto）位点。在这个TAD中，我们发现了代谢反应的遗传回路和与冬眠相关的顺式元件与邻近基因形成调控联系。小鼠中单个顺式元件的缺失会不同地改变Fto、Irx3和Irx5的表达，重塑下游基因表达程序，并以不同的方式影响代谢、睡眠、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精确定位代谢控制的功能遗传机制，并在单个cre中编码多种效应。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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