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Catherine Dulac and Steve Santoro

A hallmark of the mammalian nervous system is its 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. Such experience-triggered changes have been identified in various sensory systems, including the visual, auditory and olfactory systems, where they facilitate optimal sensory performance in diverse environments. But how do experiences produce lasting changes in the nervous system? In an exciting study just published in eLife at its official launch, Stephen Santoro and Catherine Dulac, in the Department of Molecular and Cellular Biology, provide new insights into how this process may occur in olfactory neurons. The study describes the discovery of an activity-dependent histone variant that modulates the life span of olfactory neurons and shapes the olfactory receptor repertoire as dictated by the environment.
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. While other sensory systems have to decipher only a limited collection of stimuli, the olfactory system is unusual in that it 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 olfactory sensory neuron within an individual’s nose contains just one kind of odorant receptor protein (although mammalian genomes typically encode 1000 or so different kinds of these receptors) and one way to “tune” the olfactory system to a particular environment may be to change the relative numbers of the different neuron types in the nose. Indeed, it is known that the relative abundance of each type of olfactory sensory 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. The central question then concerns how experiences regulate the expression of specific genes to cause lasting alterations to brain structure and function. One hypothesis is that the key to this process lies in changes to a neuron’s chromatin, a dynamic structure containing DNA molecules wrapped around complexes of chromosomal histones, which plays a crucial role in controlling the expression of genes.
Santoro and Dulac have now discovered a previously uncharacterized protein called H2BE, which in mice is found only in olfactory sensory neurons. H2BE is a variant of H2B, one of the five main types of histone proteins within chromatin. They found that in olfactory 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 olfactory sensory 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 expression. Consistent with this, Santoro and Dulac have found that the replacement of H2B by H2BE strongly alters gene expression, although the precise mechanism by which these alterations regulate the lifespan of neurons 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.
The work of Santoro and Dulac not only provides compelling evidence for activity-dependent epigenetic modulation of neuronal longevity, but also opens doors for studying epigenetic regulation by histone variants in other biologically relevant contexts.  It is fitting that discoveries of such caliber are published in eLife, a newly launched journal that is unique in many different ways.  Rich Losick, Harvard College Professor and Maria Moors Cabot Professor of Biology, is a member of the senior editorial team at eLife and offers his perspective on the new undertaking. “eLife is an exciting new open-access journal with several innovative features. Among these are collaborative reviews in which the editor and the reviewers come to a single consensus review. And being an electronic journal it will have innovative features such as pop-up figures in place of traditional supplemental data and movies and 3D images embedded directly in the on-line text.  eLife has lined up a terrific collection of papers for its launch and I am most proud that a member of MCB will be represented in the opening issue.”
eLife is the product of an unprecedented collaboration among three of the most prestigious research funding bodies in the world: the Howard Hughes Medical Institute, the Max Planck Society, and the Wellcome Trust.  Announced in June 2011, the journal has recruited about 200 world-renown active academic scientists from broad disciplines of life science and biomedicine to join its senior editorial team and board of reviewing editors.   A dozen research articles with considerable breadth and quality have been released at PubMed Central since October 2012.  However, the much anticipated official launch of eLife journal website will publish a collection of new research papers including that from Santoro and Dulac to further define the scope of eLife, and reveal the ultimate platform to showcase the journal content through innovative digital media.
From its conception, eLife was set to challenge traditional publishing models and to inspire change in the way scientific discoveries are communicated and shared. Its emphasis on providing the highest level of author service with a swift, fair and constructive review process has impacted the practices of more established publishing houses and its willingness to support early-career scientists has brought hope to the scientific community.  “In our experience, the review process was smooth and quick, and the reviewer comments were highly constructive, with the inclusion of thoughtful suggestions for doable experiments to address the reviewers’ concerns,” Santoro recalled. In fact, it took him just over a month to complete the experiments required for publication without further round of re-review or revision. The paper was accepted just two months from the original submission date.  
“Most importantly,” he continued, “we received a single set of reviewer comments that reflected the consensus of the reviewers.  I think that this approach offers a real advantage for scientists and should probably be used by all journals. It makes a lot of sense for the reviewers to discuss their concerns and identify the most critical ones, rather than soliciting several independent sets of comments that might be limited by the expertise and viewpoints of individual reviewers.”
It takes some faith and persuasion to publish in a brand new journal, especially when you are on the job market because its impact remains to be seen, as Santoro admits.  However, three prestigious funding agencies with great reputation and an editorial team of more than 200 world-class scientists do give you the confidence to take a bold step.  “In addition, eLife places a strong emphasis on supporting early-career scientists, as illustrated by the editors’ offer to provide a recommendation letter in support of my job search.” Santoro was pleased by the extra boost from such well-established and respected researchers in the field. When asked whether he would consider eLife again, Santoro did not hesitate: “Based on my experience so far, absolutely!

Read more in eLife

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