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Enhanced stability and polyadenylation of select mRNAs support rapid thermogenesis in the brown fat of a hibernator.

Grabek KR, Diniz Behn C, Barsh GS, Hesselberth JR, Martin SL - Elife (2015)

Bottom Line: A cohort of transcripts increased during torpor, paradoxical because transcription effectively ceases at these low temperatures.We show that this increase occurs not by elevated transcription but rather by enhanced stabilization associated with maintenance and/or extension of long poly(A) tails.This subset was enriched in a C-rich motif and genes required for BAT activation, suggesting a model and mechanism to prioritize translation of key proteins for thermogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, United States.

ABSTRACT
During hibernation, animals cycle between torpor and arousal. These cycles involve dramatic but poorly understood mechanisms of dynamic physiological regulation at the level of gene expression. Each cycle, Brown Adipose Tissue (BAT) drives periodic arousal from torpor by generating essential heat. We applied digital transcriptome analysis to precisely timed samples to identify molecular pathways that underlie the intense activity cycles of hibernator BAT. A cohort of transcripts increased during torpor, paradoxical because transcription effectively ceases at these low temperatures. We show that this increase occurs not by elevated transcription but rather by enhanced stabilization associated with maintenance and/or extension of long poly(A) tails. Mathematical modeling further supports a temperature-sensitive mechanism to protect a subset of transcripts from ongoing bulk degradation instead of increased transcription. This subset was enriched in a C-rich motif and genes required for BAT activation, suggesting a model and mechanism to prioritize translation of key proteins for thermogenesis.

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Model of BAT RNA dynamics in hibernation.Physiological stages of the torpor–arousal cycle are listed inside ofthe arrows and underneath representative animals. Key RNA changes are noted.See text for detailed explanation.DOI:http://dx.doi.org/10.7554/eLife.04517.018
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fig7: Model of BAT RNA dynamics in hibernation.Physiological stages of the torpor–arousal cycle are listed inside ofthe arrows and underneath representative animals. Key RNA changes are noted.See text for detailed explanation.DOI:http://dx.doi.org/10.7554/eLife.04517.018

Mentions: Our data suggest a model (Figure 7) of RNAdynamics in hibernator BAT wherein key RNAs for BAT function are selectively stabilizedduring torpor while bulk transcripts decline through degradation in the absence of newtranscription. Stabilization likely occurs by a temperature-dependent protectivemechanism that is in place before body temperature reaches 5°C, such as PCPB3binding to the 3′ UTRs of protected transcripts, which then leads to theirrelative increase as torpor progresses. At the end of torpor and onset of arousal, thestabilized mRNA subset with the longest poly(A) tails is translated immediately as BATtemperature becomes permissive. As BAT temperature rises, further polyadenylation of theremaining stabilized RNAs facilitates their translation, transcription resumes (Osborne et al., 2004), and, during interboutarousal, transcripts that were previously degraded during torpor are replenished totheir baseline levels. This dynamic cycle of transcription, degradation, stabilization,and polyadenylation in BAT leads to translation of the correct transcripts at thecorrect time with minimal energy expenditure. Specifically: (1) energy intensivetranslation during early arousal is directed to proteins needed for BAT activation; (2)the cell is not dependent on de novo transcription at the onset of the short bursts ofmetabolic activity, which could delay thermogenesis and induce stress; (3) inhibition oftranslation via shortening of poly(A) tails while body temperature is high or begins todecline conserves energy compared to mRNA degradation and subsequent re-synthesis. Thus,given a general suppression of transcription by low body temperature during two-weektorpor periods, stabilization and dynamic polyadenylation provide an alternativemechanism to prioritize transcripts for immediate translation when BAT metabolicactivity rapidly resumes.10.7554/eLife.04517.018Figure 7.Model of BAT RNA dynamics in hibernation.


Enhanced stability and polyadenylation of select mRNAs support rapid thermogenesis in the brown fat of a hibernator.

Grabek KR, Diniz Behn C, Barsh GS, Hesselberth JR, Martin SL - Elife (2015)

Model of BAT RNA dynamics in hibernation.Physiological stages of the torpor–arousal cycle are listed inside ofthe arrows and underneath representative animals. Key RNA changes are noted.See text for detailed explanation.DOI:http://dx.doi.org/10.7554/eLife.04517.018
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383249&req=5

fig7: Model of BAT RNA dynamics in hibernation.Physiological stages of the torpor–arousal cycle are listed inside ofthe arrows and underneath representative animals. Key RNA changes are noted.See text for detailed explanation.DOI:http://dx.doi.org/10.7554/eLife.04517.018
Mentions: Our data suggest a model (Figure 7) of RNAdynamics in hibernator BAT wherein key RNAs for BAT function are selectively stabilizedduring torpor while bulk transcripts decline through degradation in the absence of newtranscription. Stabilization likely occurs by a temperature-dependent protectivemechanism that is in place before body temperature reaches 5°C, such as PCPB3binding to the 3′ UTRs of protected transcripts, which then leads to theirrelative increase as torpor progresses. At the end of torpor and onset of arousal, thestabilized mRNA subset with the longest poly(A) tails is translated immediately as BATtemperature becomes permissive. As BAT temperature rises, further polyadenylation of theremaining stabilized RNAs facilitates their translation, transcription resumes (Osborne et al., 2004), and, during interboutarousal, transcripts that were previously degraded during torpor are replenished totheir baseline levels. This dynamic cycle of transcription, degradation, stabilization,and polyadenylation in BAT leads to translation of the correct transcripts at thecorrect time with minimal energy expenditure. Specifically: (1) energy intensivetranslation during early arousal is directed to proteins needed for BAT activation; (2)the cell is not dependent on de novo transcription at the onset of the short bursts ofmetabolic activity, which could delay thermogenesis and induce stress; (3) inhibition oftranslation via shortening of poly(A) tails while body temperature is high or begins todecline conserves energy compared to mRNA degradation and subsequent re-synthesis. Thus,given a general suppression of transcription by low body temperature during two-weektorpor periods, stabilization and dynamic polyadenylation provide an alternativemechanism to prioritize transcripts for immediate translation when BAT metabolicactivity rapidly resumes.10.7554/eLife.04517.018Figure 7.Model of BAT RNA dynamics in hibernation.

Bottom Line: A cohort of transcripts increased during torpor, paradoxical because transcription effectively ceases at these low temperatures.We show that this increase occurs not by elevated transcription but rather by enhanced stabilization associated with maintenance and/or extension of long poly(A) tails.This subset was enriched in a C-rich motif and genes required for BAT activation, suggesting a model and mechanism to prioritize translation of key proteins for thermogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, United States.

ABSTRACT
During hibernation, animals cycle between torpor and arousal. These cycles involve dramatic but poorly understood mechanisms of dynamic physiological regulation at the level of gene expression. Each cycle, Brown Adipose Tissue (BAT) drives periodic arousal from torpor by generating essential heat. We applied digital transcriptome analysis to precisely timed samples to identify molecular pathways that underlie the intense activity cycles of hibernator BAT. A cohort of transcripts increased during torpor, paradoxical because transcription effectively ceases at these low temperatures. We show that this increase occurs not by elevated transcription but rather by enhanced stabilization associated with maintenance and/or extension of long poly(A) tails. Mathematical modeling further supports a temperature-sensitive mechanism to protect a subset of transcripts from ongoing bulk degradation instead of increased transcription. This subset was enriched in a C-rich motif and genes required for BAT activation, suggesting a model and mechanism to prioritize translation of key proteins for thermogenesis.

Show MeSH
Related in: MedlinePlus