Enhanced stability and polyadenylation of select mRNAs support rapid thermogenesis in the brown fat of a hibernator.
Enhanced stability and polyadenylation of select mRNAs support rapid thermogenesis in the brown fat of a hibernator.
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DOI：
10.7554/elife.04517
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发表时间：
2015-01-27
期刊：
影响因子：
7.7
通讯作者：
Martin SL
中科院分区：
文献类型：
--
作者：
Grabek KR;Diniz Behn C;Barsh GS;Hesselberth JR;Martin SL
在冬眠期间，动物在麻木和觉醒之间循环。这些周期涉及在基因表达水平上的动态生理调节的戏剧性但知之甚少的机制。每个周期，棕色脂肪组织（BAT）通过产生必要的热量来驱动周期性的唤醒。我们将数字转录组分析应用于精确定时的样本，以确定冬眠蝙蝠强烈活动周期的分子途径。一个队列的成绩单增加在麻木，矛盾的是，因为转录有效地停止在这些低温。我们表明，这种增加发生不是由转录升高，而是由增强稳定与维护和/或延长长聚（A）尾。数学建模进一步支持温度敏感机制，以保护转录物的子集免受正在进行的批量降解，而不是增加转录。该子集富含富含C基序和BAT激活所需的基因，这表明了优先翻译产热关键蛋白的模型和机制。http://dx.doi.org/10.7554/eLife.04517.001许多哺乳动物冬眠是为了避免食物短缺和冬季的恶劣条件。冬眠涉及进入一种称为麻木的状态，这会大大减少身体使用的能量。在麻痹期间，体温也会降低。这在地松鼠中尤其明显，它们的体温可以徘徊在冰点以上甚至以下。然而，冬眠的哺乳动物不能在冬眠的几个月里持续保持这种状态，而是在持续1-3周的麻痹和持续12-24小时的短暂“觉醒”之间循环，在此期间，它们的身体迅速变暖。冬眠动物开始热身所需的热量来自一种特殊形式的脂肪，称为棕色脂肪组织。通常，产生这种热量所需的代谢活动的爆发取决于某些蛋白质的产生。制造蛋白质涉及从称为信使RNA（mRNA）的模板分子“翻译”其序列，这些模板分子是从编码蛋白质的基因“转录”的。当身体处于低温时，这两个过程都停止了。那么，冬眠者是如何在冬眠的唤醒期快速有效地使自己升温的呢？Grabek等人通过分析冬眠的13线地松鼠棕色脂肪组织中mRNA的相对水平来研究这一点。Grabek等人使用一种特殊的技术对取自棕色脂肪组织的mRNA小片段进行取样和测序，编制了一份存在于休眠-觉醒周期不同时间点的mRNA分子谱，并将其与取自非冬眠松鼠的类似谱进行了比较。通过这项分析，Grabek等人检测到，即使体温低到足以停止基因转录，在麻痹期间，产生热量所需的一组特定mRNA分子的丰度也会增加。这种丰度的增加并不是因为产生了更多的mRNA分子;相反，mRNA分子被修饰成更稳定和持久。一旦动物在唤醒过程中变暖，基因转录就会重新激活，并产生更多新的mRNA分子。Grabek等人认为，棕色脂肪组织功能所需的关键mRNA在休眠期间通过温度依赖性保护机制选择性稳定。这些mRNA在唤醒过程中优先翻译成蛋白质，以快速有效地加热冬眠动物。大多数其他mRNA分子在整个休眠过程中都会降解，因此它们的数量会下降，因为直到体温在唤醒过程中短暂恢复时，它们才被转录。这种保护机制是否也用于其他组织在麻痹仍然是一个问题，为未来的工作。DOI：http://dx.doi.org/10.7554/eLife.04517.002网站
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. DOI: http://dx.doi.org/10.7554/eLife.04517.001 Many mammals hibernate to avoid food scarcity and harsh conditions during winter. Hibernation involves entering a state called torpor, which drastically reduces the amount of energy used by the body. During torpor, body temperature also decreases. This is particularly exemplified in ground squirrels, whose body temperature can hover at just above or even below the point of freezing. However, hibernating mammals cannot remain in this state continuously over the months of hibernation but instead cycle between bouts of torpor lasting for 1–3 weeks and brief periods of ‘arousal’ lasting between 12–24 hr, during which their body rapidly warms up. The heat required to start warming up the hibernator is generated from a specialized form of fat called brown adipose tissue. Normally, the bursts of metabolic activity that are required to create this heat depend on certain proteins being produced. Making a protein involves ‘translating’ its sequence from template molecules called messenger RNA (mRNA), which are ‘transcribed’ from the gene that encodes the protein. During the low body temperatures experienced during torpor, both of these processes stop. So how is the hibernator able to quickly and efficiently heat itself up during the arousal periods of hibernation? Grabek et al. investigated this by analyzing the relative levels of mRNA in the brown adipose tissue of hibernating 13-lined ground squirrels. Using a special technique to sample and sequence small fragments of mRNA taken from brown adipose tissue, Grabek et al. compiled a profile of the mRNA molecules present at different points in the torpor–arousal cycle and compared this with a similar profile taken from squirrels that were not hibernating. From this analysis, Grabek et al. detected that a particular group of mRNA molecules that are required for producing heat increase in abundance during torpor, even though body temperature is low enough to stop gene transcription. This increased abundance does not occur because more of the mRNA molecules are made; instead, the mRNA molecules are modified to become more stable and long lasting. Once the animal warms up during arousal, gene transcription is reactivated and more new mRNA molecules are made. Grabek et al. suggest that the key mRNAs required for brown adipose tissue function are selectively stabilized during torpor through a temperature-dependent protective mechanism. These mRNAs are then preferentially translated into proteins during arousal to rapidly and efficiently heat the hibernator. Most other mRNA molecules degrade throughout torpor, and so their numbers decline as replacements are not transcribed until body temperature briefly recovers during arousal. Whether this protective mechanism is also used in other tissues during torpor remains a question for future work. DOI: http://dx.doi.org/10.7554/eLife.04517.002