Liver Transcriptome Dynamics During Hibernation Are Shaped by a Shifting Balance Between Transcription and RNA Stability

Abstract

Hibernators dramatically lower metabolism to save energy while fasting for months. Prolonged fasting challenges metabolic homeostasis, yet small-bodied hibernators emerge each spring ready to resume all aspects of active life, including immediate reproduction. The liver is the body’s metabolic hub, processing and detoxifying macromolecules to provide essential fuels to brain, muscle and other organs throughout the body. Here we quantify changes in liver gene expression across several distinct physiological states of hibernation in 13-lined ground squirrels, using RNA-seq to measure the steady-state transcriptome and GRO-seq to measure transcription for the first time in a hibernator. Our data capture key timepoints in both the seasonal and torpor-arousal cycles of hibernation. Strong positive correlation between transcription and the transcriptome indicates that transcriptional control dominates the known seasonal reprogramming of metabolic gene expression in liver for hibernation. During the torpor-arousal cycle, however, discordance develops between transcription and the steady-state transcriptome by at least two mechanisms: 1) although not transcribed during torpor, some transcripts are unusually stable across the torpor bout; and 2) unexpectedly, on some genes, our data suggest continuing, slow elongation with a failure to terminate transcription across the torpor bout. While the steady-state RNAs corresponding to these read through transcripts did not increase during torpor, they did increase shortly after rewarming despite their simultaneously low transcription. Both of these mechanisms would assure the immediate availability of functional transcripts upon rewarming. Integration of transcriptional, post-transcriptional and RNA stability control mechanisms, all demonstrated in these data, likely initiate a serial gene expression program across the short euthermic period that restores the tissue and prepares the animal for the next bout of torpor.

Investigating the effects of chronic low-dose radiation exposure in the liver of a hypothermic zebrafish model

“…This is supported by studies in mice demonstrating that mice preconditioned with sub-lethal ischemia before more severe ischemia can increase ischemic tolerance through induction of DNA repair mechanisms 91 . To continue, when observing hibernating animals, transcriptomic studies of the liver in hibernating 13-lined ground squirrels (Ictidomys tridecemlineatus) also found enrichment of genes involved in double-strand break repair with upregulation of genes such as DDX11 that were correlated with colder body temperatures 92 . Similar observations were made by Jenson et al, who reported DNA repair-related GO terms in the liver of hibernating grizzly bears (Ursus arctos horribilis) involving serval DNA repair (e.g.…”

Adapting to stress: The effects of hibernation and hibernacula temperature on the hepatic transcriptome of Rhinolophus pusillus

“…In animals, the expression or repression of certain genes modulates hibernation processes and adaptive evolution. For example, in the livers of thirteen‐lined ground squirrels, the expression of genes associated with fatty acid, cholesterol and steroid biosynthesis, xenobiotic, and amino acid metabolism were reduced 13 . In Arctic ground squirrels, high expression of Pck1 , a crucial enzyme of gluconeogenesis, coupled with low expression of Gck , was observed to improve energy distribution during hibernation 14 .…”

Impacts of seasonality on gene expression in the Chinese horseshoe bat

“…To test for tissue specificity of gene expression, we sampled three different tissues (brain, cochlea, and liver) for each individual. Brain and liver were commonly used to investigate seasonal differences in gene expression (e.g., Gillen et al, 2021 ; Johnston et al, 2016 ; Schwartz et al, 2013 ; Xiao et al, 2015 ; Zhao et al, 2016 ). In this study, we also included cochlea tissue because previous studies have indicated seasonal changes in echolocation calls and auditory processing in bats (Grilliot et al, 2014 ; Miller et al, 2016 ).…”