The activity-dependent histone variant H2BE modulates the life span of olfactory neurons.
The activity-dependent histone variant H2BE modulates the life span of olfactory neurons.
复制标题
DOI：
10.7554/elife.00070
复制
发表时间：
2012-12-13
期刊：
影响因子：
7.7
通讯作者：
Dulac C
中科院分区：
文献类型：
--
作者：
Santoro SW;Dulac C
我们已经确定了一个复制不依赖的组蛋白变异体，组蛋白2h2be(在这里被称为h2be)，它只由嗅觉化学感觉神经元表达。在嗅觉神经元中，H_2BE的水平是不同的，但根据共表达的嗅觉受体(OR)的特性而定型。功能获得和功能丧失实验表明，H_2be表达的变化影响成年嗅觉上皮的嗅觉功能和OR表征。我们发现，感觉活动减少了H2BE的表达，并促进了神经细胞的死亡，因此不活跃的嗅觉神经元表现出更高水平的变异和更短的寿命。H_2BE的翻译后修饰(PTM)不同于典型的H_2B，这与H_2BE在改变转录中的作用是一致的。我们提出了H_2BE在调节嗅觉神经元种群动态中的一种生理功能，以使OR谱系适应环境。DOI：http://dx.doi.org/10.7554/eLife.00070.001所有哺乳动物神经系统的一个标志是它们经历由经验塑造的功能变化的能力。这种现象是我们大脑正常发育和学习能力的基础，也使各种感官系统--包括视觉、听觉和嗅觉系统--在不同的环境中表现最佳。在大多数哺乳动物中，高功能的嗅觉系统对于执行对生存至关重要的任务至关重要，如寻找食物、躲避捕食者和交配。一般来说，感官系统只需要破译有限的刺激集合，但嗅觉系统必须能够从给定环境中发现的数千种不同的气味中处理信息，这些气味在不同的环境中可能会有巨大的差异。哺乳动物鼻子中的每个嗅觉神经元只包含一种气味受体蛋白，尽管哺乳动物的基因组通常编码大约1000种不同的受体蛋白。这表明，通过改变不同类型神经元的相对数量，可能会使嗅觉系统适应特定的环境。事实上，众所周知，每种类型的嗅觉神经元的相对丰度都会随着年龄和经验的变化而变化，这些变化可能是由神经元寿命的变化引起的。尽管我们对这些经验依赖的变化是如何在分子水平上协调的理解还远未完成，但很明显，调整特定基因产物的水平是必要的。但体验如何改变基因产物的水平，从而引起大脑的持久变化呢？一种假设是，一种名为染色质的结构的变化是这一过程的关键：染色质是DNA分子的集合，DNA分子相当长，并组织蛋白质，主要是被称为组蛋白的蛋白质，这些蛋白质一起形成一个紧凑的结构，可以装入细胞核内。Santoro和Dulac现在发现了一种以前没有特征的蛋白质，称为H2BE，只在小鼠的嗅觉神经元中发现。H_2BE是一种叫做H_2B的蛋白质的变体，H_2B是一种广为人知的组蛋白。他们发现，在嗅觉神经元中，H_2BE取代H_2B的程度取决于神经元经历的活动量：在高度活跃的神经元中几乎检测不到H_2BE，但在不活跃的神经元中几乎完全取代H_2B。此外，基因操作表明，H2BE的缺失显著延长了神经元的寿命，而H2BE水平的升高则缩短了神经元的寿命。这些发现揭示了一个非同寻常的过程，即随着时间的推移，不活跃的嗅觉神经元相对于活跃的神经元被耗尽。H_2BE与H_2B只有五个氨基酸的区别，它是如何导致神经元组成发生如此戏剧性的变化的？有证据表明，这些氨基酸会破坏染色质和调节基因活性的“效应器”蛋白之间的相互作用。与此一致的是，Santoro和Dulac发现，H_2B被H_2BE取代会强烈改变基因活性，尽管这些改变调节神经元寿命的确切机制仍有待确定。详细了解这一过程，并探索神经系统其他部位的经验依赖性变化是否涉及类似的现象，是未来研究的有趣领域。DOI：http://dx.doi.org/10.7554/eLife.00070.002
We have identified a replication-independent histone variant, Hist2h2be (referred to herein as H2be), which is expressed exclusively by olfactory chemosensory neurons. Levels of H2BE are heterogeneous among olfactory neurons, but stereotyped according to the identity of the co-expressed olfactory receptor (OR). Gain- and loss-of-function experiments demonstrate that changes in H2be expression affect olfactory function and OR representation in the adult olfactory epithelium. We show that H2BE expression is reduced by sensory activity and that it promotes neuronal cell death, such that inactive olfactory neurons display higher levels of the variant and shorter life spans. Post-translational modifications (PTMs) of H2BE differ from those of the canonical H2B, consistent with a role for H2BE in altering transcription. We propose a physiological function for H2be in modulating olfactory neuron population dynamics to adapt the OR repertoire to the environment. DOI: http://dx.doi.org/10.7554/eLife.00070.001 A hallmark of the nervous systems of all mammals is their capacity to undergo changes in function that are shaped by experience. This phenomenon underlies the ability of our brains to develop properly and to learn, and also enables various sensory systems—including the visual, auditory and olfactory systems—to perform optimally in diverse environments. In most mammals, a high-functioning olfactory system is essential for carrying out tasks that are crucial for survival, such as finding food, avoiding predators and mating. In general, sensory systems have to decipher only a limited collection of stimuli, but the olfactory system must be able to process information from thousands of distinct odors that are found in a given environment and which may vary dramatically from one environment to the next. Each odor-sensing neuron in the nose of a mammal contains just one kind of odorant receptor protein, although mammalian genomes typically encode 1000 or so different kinds of receptor proteins. This suggests that it might be possible to ‘tune’ the olfactory system to a particular environment by changing the relative numbers of the different types of neurons. Indeed, it is known that the relative abundance of each type of odor-sensing neuron changes with age and experience, and that these changes might be caused by variations in the lifespans of the neurons. Although our understanding of how these experience-dependent changes are orchestrated at the molecular level is far from complete, it is clear that adjustments in the levels of specific gene products is necessary. But how do experiences alter the levels of gene products to give rise to lasting changes in the brain? One hypothesis is that changes to a structure called chromatin are key to this process: chromatin is an assembly of DNA molecules, which are quite long, and organizing proteins, mostly proteins known as histones, that together form a compact structure that can fit inside the nucleus of a cell. Santoro and Dulac have now discovered a previously uncharacterized protein called H2BE that is found only in the odor-sensing neurons of mice. H2BE is a variant of a protein called H2B, which is a well-known histone. They found that in odor-sensing neurons, H2BE replaces H2B to an extent that depends on the amount of activity experienced by the neuron: H2BE is nearly undetectable in highly active neurons, but almost completely replaces H2B in neurons that are inactive. Moreover, genetic manipulation showed that the deletion of H2BE significantly extended the lifespan of neurons, whereas elevated levels of H2BE shortened their lifespan. These findings reveal an extraordinary process that involves inactive odor-sensing neurons being depleted relative to active ones over time. How does H2BE, which differs from H2B by just five amino acids, cause such dramatic changes in neuronal composition? One hint comes from evidence that these amino acids disrupt interactions between chromatin and ‘effector’ proteins, which modulate gene activity. Consistent with this, Santoro and Dulac have found that the replacement of H2B by H2BE strongly alters gene activity, although the precise mechanism by which these alterations regulate neuronal lifespans remains to be determined. Understanding this process in detail, and exploring if similar phenomena are involved in experience-dependent changes elsewhere in the nervous system, are fascinating areas of future research. DOI: http://dx.doi.org/10.7554/eLife.00070.002