An Epigenetic Signature for Monoallelic Olfactory Receptor Expression

Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158, USA.
Cell (Impact Factor: 32.24). 05/2011; 145(4):555-70. DOI: 10.1016/j.cell.2011.03.040
Source: PubMed


Constitutive heterochromatin is traditionally viewed as the static form of heterochromatin that silences pericentromeric and telomeric repeats in a cell cycle- and differentiation-independent manner. Here, we show that, in the mouse olfactory epithelium, olfactory receptor (OR) genes are marked in a highly dynamic fashion with the molecular hallmarks of constitutive heterochromatin, H3K9me3 and H4K20me3. The cell type and developmentally dependent deposition of these marks along the OR clusters are, most likely, reversed during the process of OR choice to allow for monogenic and monoallelic OR expression. In contrast to the current view of OR choice, our data suggest that OR silencing takes place before OR expression, indicating that it is not the product of an OR-elicited feedback signal. Our findings suggest that chromatin-mediated silencing lays a molecular foundation upon which singular and stochastic selection for gene expression can be applied.

Download full-text


Available from: Gilad Barnea, Apr 22, 2014
  • Source
    • "Moreover, we cannot exclude that indirect effects from these genetic manipulations convolute the interpretation of our analysis. However, our previous work showed that, in OSNs, H3K9me3 is deposited almost exclusively on OR genes and pericentromeric and subtelomeric repeats (Magklara et al., 2011). In agreement with this, our RNA-seq data from G9a/Glp KO mice suggest that, by and large, only OR genes are significantly affected by this deletion. "
    [Show abstract] [Hide abstract]
    ABSTRACT: An astounding property of the nervous system is its cellular diversity. This diversity, which was initially realized by morphological and electrophysiological differences, is ultimately produced by variations in gene-expression programs. In most cases, these variations are determined by external cues. However, a growing number of neuronal types have been identified in which inductive signals cannot explain the few but decisive transcriptional differences that cause cell diversification. Here, we show that heterochromatic silencing, which we find is governed by histone methyltransferases G9a (KMT1C) and GLP (KMT1D), is essential for stochastic and singular olfactory receptor (OR) expression. Deletion of G9a and GLP dramatically reduces the complexity of the OR transcriptome, resulting in transcriptional domination by a few ORs and loss of singularity in OR expression. Thus, our data suggest that, in addition to its previously known functions, heterochromatin creates an epigenetic platform that affords stochastic, mutually exclusive gene choices and promotes cellular diversity.
    Full-text · Article · Nov 2014 · Cell Reports
  • 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.
    Full-text · Article · Jun 2014 · Frontiers in Neuroscience
  • Source
    • "In the mammalian central nervous system, each olfactory sensory neuron expresses only one olfactory receptor (OR) from a family of ∼1200 genes (Buck and Axel, 1991). Before an OR gene is expressed, all alleles are silenced and converted to heterochromatin (Magklara et al., 2011). A limiting enzymatic activity then stochastically removes the heterochromatin marks from one allele to activate it. "
    [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:
    Full-text · Article · May 2014 · eLife Sciences
Show more