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

Area of Science:

• Genomics
• Evolutionary Biology
• Metabolic Research

Background:

• Mammalian hibernation involves complex physiological adaptations.
• Conserved cis-elements play crucial roles in gene regulation and evolution.
• The Fat Mass & Obesity (Fto) locus is implicated in metabolic regulation.

Purpose of the Study:

• To elucidate the functional roles of conserved cis-elements in mammalian hibernation evolution.
• To investigate the impact of cis-elements on gene expression and metabolic control.
• To understand the behavioral and obesogenic effects of specific cis-elements.

Main Methods:

• Genomic analyses to identify topologically associated domains (TADs) with convergent changes in hibernators.
• Gene knockout studies in mice to assess cis-element function.
• Phenotypic profiling across hibernation states and dietary challenges.

Main Results:

• Identified TADs, including the Fto locus, with significant convergent genomic changes in hibernators.
• Demonstrated that hibernation-linked cis-elements regulate Fto, Irx3, and Irx5 gene expression, affecting downstream genes.
• Discovered distinct roles for cis-elements in metabolic control during different hibernation phases and varying diets.
• Showcased one cis-element's influence on lean phenotype and foraging behavior.

Conclusions:

• Convergent evolution in hibernators highlights functional genetic mechanisms of mammalian metabolic control.
• Specific cis-elements are critical for regulating metabolism, obesity, and behavior.
• These findings provide insights into the genetic basis of hibernation and metabolic adaptation.