Conserved Noncoding Cis-Elements Associated with Hibernation Modulate Metabolic and Behavioral Adaptations in Mice

Steinwand, S.; Stacher Horndli, C.; Ferris, E.; Emery, J.; Murcia, J. D. G.; Rodriguez, A. C.; Leydsman, T. C.; Chaix, A.; Thomas, A.; Davey, C.; Gregg, C.

doi:10.1101/2024.06.26.600851

bioRxiv · 10.1101/2024.06.26.600851

Conserved Noncoding Cis-Elements Associated with Hibernation Modulate Metabolic and Behavioral Adaptations in Mice

Steinwand, S.·Stacher Horndli, C.·Ferris, E.·Emery, J.·Murcia, J. D. G.·Rodriguez, A. C.·Leydsman, T. C.·Chaix, A.·Thomas, A.·Davey, C.·Gregg, C.

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Abstract

Our study elucidates functional roles for conserved cis-elements associated with the evolution of mammalian hibernation. Genomic analyses found topologically associated domains (TADs) that disproportionately accumulated convergent genomic changes in hibernators, including the TAD for the Fat Mass & Obesity (Fto) locus. Some hibernation-linked cis-elements in this TAD form regulatory contacts with multiple neighboring genes. Knockout mice for these cis-elements exhibit Fto, Irx3, and Irx5 gene expression changes, impacting hundreds of genes downstream. Profiles of pre-torpor, torpor, and post-torpor phenotypes found distinct roles for each cis-element in metabolic control, while a high caloric diet uncovered different obesogenic effects. One cis-element promoting a lean phenotype influences foraging behaviors throughout life, affecting specific behavioral sequences. Thus, convergent evolution in hibernators pinpoints functional genetic mechanisms of mammalian metabolic control. One-sentence summaryDeletions of conserved cis-elements tied to hibernator evolution causes diverse metabolic traits in mice.

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Steinwand, S., Stacher Horndli, C., Ferris, E., Emery, J., Murcia, J. D. G., Rodriguez, A. C., Leydsman, T. C., Chaix, A., Thomas, A., Davey, C., Gregg, C.. 2024-06-27. Conserved Noncoding Cis-Elements Associated with Hibernation Modulate Metabolic and Behavioral Adaptations in Mice. https://doi.org/10.1101/2024.06.26.600851

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