An Epigenetic Trap Stabilizes Singular Olfactory Receptor Expression

Tetrad Program, University of California, San Francisco, San Francisco, CA 94158, USA.
Cell (Impact Factor: 32.24). 07/2013; 154(2):325-36. DOI: 10.1016/j.cell.2013.06.039
Source: PubMed


The molecular mechanisms regulating olfactory receptor (OR) expression in the mammalian nose are not yet understood. Here, we identify the transient expression of histone demethylase LSD1 and the OR-dependent expression of adenylyl cyclase 3 (Adcy3) as requirements for initiation and stabilization of OR expression. As a transcriptional coactivator, LSD1 is necessary for desilencing and initiating OR transcription, but as a transcriptional corepressor, it is incompatible with maintenance of OR expression, and its downregulation is imperative for stable OR choice. Adcy3, a sensor of OR expression and a transmitter of an OR-elicited feedback, mediates the downregulation of LSD1 and promotes the differentiation of olfactory sensory neurons (OSNs). This novel, three-node signaling cascade locks the epigenetic state of the chosen OR, stabilizes its singular expression, and prevents the transcriptional activation of additional OR alleles for the life of the neuron.

Download full-text


Available from: David B. Lyons, May 02, 2014
22 Reads
  • Source
    • "The stem cells in the olfactory epithelia are capable of generating neurons as well as supporting (glial) cells (Leung et al., 2007). The neurons that are generated choose a receptor “identity”; each sensory neuron usually expresses a single vomeronasal or odorant receptor, and this gene choice is highly regulated (Shykind et al., 2004; Lomvardas et al., 2006; Magklara et al., 2011; Lyons et al., 2013). In addition, the developmental process of aging regulates olfactory neurogenesis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurogenesis continues well beyond embryonic and early postnatal ages in three areas of the nervous system. The subgranular zone supplies new neurons to the dentate gyrus of the hippocampus. The subventricular zone supplies new interneurons to the olfactory bulb, and the olfactory neuroepithelia generate new excitatory sensory neurons that send their axons to the olfactory bulb. The latter two areas are of particular interest as they contribute new neurons to both ends of a first-level circuit governing olfactory perception. The vomeronasal organ and the main olfactory epithelium comprise the primary peripheral olfactory epithelia. These anatomically distinct areas share common features, as each exhibits extensive neurogenesis well beyond the juvenile phase of development. Here we will discuss the effect of age on the structural and functional significance of neurogenesis in the vomeronasal and olfactory epithelia, from juvenile to advanced adult ages, in several common model systems. We will next discuss how age affects the regenerative capacity of these neural stem cells in response to injury. Finally, we will consider the integration of newborn neurons into an existing circuit as it is modified by the age of the animal.
    Frontiers in Neuroscience 06/2014; 8(8):182. DOI:10.3389/fnins.2014.00182 · 3.66 Impact Factor
  • Source
    • "A limiting enzymatic activity then stochastically removes the heterochromatin marks from one allele to activate it. The expressed OR protein mediates a feedback loop that inhibits removal of heterochromatin marks from all other alleles, preventing their transcription (Serizawa et al., 2003; Lyons et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: eLife digest African sleeping sickness is a potentially lethal disease that is caused by a parasite called T. brucei and spread by tsetse flies. Like many of the parasites that cause tropical diseases, T. brucei employs genetic trickery to evade the immune systems of humans and other mammals. This involves changing the variant surface glycoprotein (VSG) coat that surrounds the parasite on a regular basis in order to remain one step ahead of the immune system of its host: while the immune system looks for invaders wearing a particular coat, the parasites are spreading through the host in a completely different coat. To infect other hosts, the parasite must undergo changes that allow it to re-infect the tsetse fly. Therefore, besides the ‘antigenic variation’ that allows it to change its surface coat when it is in the blood of its host, T. brucei must undergo a more fundamental metamorphosis before it is capable of colonizing the tsetse fly. However, many details of the changes that allow the parasites to re-infect flies are not understood. T. brucei has several hundred VSG genes clustered in about 15 regions known as expression sites, but only a single expression site is active at any given time. Each expression site also contains a number of other genes known as expression site-associated genes (ESAGs). Antigenic variation can occur as a result of different VSG genes within the same expression site being expressed as proteins, or when the active expression site is silenced and another expression site is activated. This is another process that is not fully understood. Batram et al. now reveal that the expression of VSG genes, antigenic variation and the changes that allow the parasites to re-infect flies are all related to each other. This suggests that the expression site could provide a new point of attack in the fight against African sleeping sickness. DOI:
    eLife Sciences 05/2014; 3(3):e02324. DOI:10.7554/eLife.02324 · 9.32 Impact Factor
  • Nature Reviews Neuroscience 08/2013; 14(9). DOI:10.1038/nrn3572 · 31.43 Impact Factor
Show more