Hibernation impacts lysine methylation dynamics in the 13-lined ground squirrel, Ictidomys tridecemlineatus

During winter hibernation in mammals, body temperature falls to near-ambient levels, metabolism shifts to favor lipid oxidation, and metabolic rate is strongly suppressed by inhibiting many ATP-expensive processes (e.g., transcription, translation) for animals in order to survive for many months on limited reserves of body fuels. Regulation of such profound changes (i.e., metabolic rate depression) requires rapid and reversible controls provided by protein posttranslational modifications. Protein lysine methylation provides one mechanism by which the functionality, activity, and stability of cellular proteins and enzymes can be modified for the needs of the hibernator. The present study reports the responses of seven lysine methyltransferases (SMYD2, SUV39H1, SET8, SET7/9, G9a, ASH2L, and RBBP5) in skeletal muscle and liver over seven stages of the torpor/arousal cycle in 13-lined ground squirrels (Ictidomys tridecemlineatus). A tissue-specific and stage-specific analysis revealed significant changes in the protein levels of lysine methyltransferases, methylation patterns on histone H3, histone methyltransferase activity, and methylation of the p53 transcription factor. Enzymes typically increased in protein amount in either torpor, arousal, or the transitory periods. Methylation of histone H3 and p53 typically followed the patterns of the methyltransferase enzymes. Overall, these data show that protein lysine methylation is an important regulator of the mammalian hibernation phenotype.