Dynamic RNA Regulation in the Brain Underlies Physiological Plasticity in a Hibernating Mammal

Rui Fu; Austin E Gillen; Katharine R Grabek; Kent A Riemondy; L Elaine Epperson; Carlos D Bustamante; Jay R Hesselberth; Sandra L Martin

doi:10.3389/fphys.2020.624677

Dynamic RNA Regulation in the Brain Underlies Physiological Plasticity in a Hibernating Mammal

Front Physiol. 2021 Jan 18:11:624677. doi: 10.3389/fphys.2020.624677. eCollection 2020.

Authors

Rui Fu¹, Austin E Gillen¹, Katharine R Grabek^{2

3}, Kent A Riemondy¹, L Elaine Epperson⁴, Carlos D Bustamante³, Jay R Hesselberth^{1

5}, Sandra L Martin^{1

6}

Affiliations

¹ RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, United States.
² Fauna Bio Incorporated, Emeryville, CA, United States.
³ Department of Biomedical Data Science, Stanford University, Stanford, CA, United States.
⁴ Center for Genes, Environment & Health, National Jewish Health, Denver, CO, United States.
⁵ Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado, Aurora, CO, United States.
⁶ Department of Cell & Developmental Biology, School of Medicine, University of Colorado, Aurora, CO, United States.

Abstract

Hibernation is a physiological and behavioral phenotype that minimizes energy expenditure. Hibernators cycle between profound depression and rapid hyperactivation of multiple physiological processes, challenging our concept of mammalian homeostasis. How the hibernator orchestrates and survives these extremes while maintaining cell to organismal viability is unknown. Here, we enhance the genome integrity and annotation of a model hibernator, the 13-lined ground squirrel. Our new assembly brings this genome to near chromosome-level contiguity and adds thousands of previously unannotated genes. These new genomic resources were used to identify 6,505 hibernation-related, differentially-expressed and processed transcripts using RNA-seq data from three brain regions in animals whose physiological status was precisely defined using body temperature telemetry. A software tool, squirrelBox, was developed to foster further data analyses and visualization. SquirrelBox includes a comprehensive toolset for rapid visualization of gene level and cluster group dynamics, sequence scanning of k-mer and domains, and interactive exploration of gene lists. Using these new tools and data, we deconvolute seasonal from temperature-dependent effects on the brain transcriptome during hibernation for the first time, highlighting the importance of carefully timed samples for studies of differential gene expression in hibernation. The identified genes include a regulatory network of RNA binding proteins that are dynamic in hibernation along with the composition of the RNA pool. In addition to passive effects of temperature, we provide evidence for regulated transcription and RNA turnover during hibernation. Significant alternative splicing, largely temperature dependent, also occurs during hibernation. These findings form a crucial first step and provide a roadmap for future work toward defining novel mechanisms of tissue protection and metabolic depression that may 1 day be applied toward improving human health.

Keywords: ARE binding proteins; AU-rich element (ARE); Ictidomys tridecemlineatus; RNA binding protein; forebrain; hypothalamus; medulla; pre-miRNA.

Abstract

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