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.

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Available from: David B. Lyons, May 02, 2014
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    • "Furthermore, it is well recognized that a feedback loop elicited by expression of the chosen functional OR gene maintains the selection and inhibits further activation of other OR genes (Alsing and Sneppen, 2013; Dalton et al., 2013; Kolterman et al., 2012; Lewcock and Reed, 2004; Lyons et al., 2013; Nguyen et al., 2007; Serizawa et al., 2003; Tan et al., 2013). Recent studies reveal that expression of the winning allele causes endoplasmic reticulum stress and expression of Adcy3 enzyme, which then down-regulates LSD1, leading to an epigenetic trap that stabilizes the OR choice (Lyons et al., 2013). "
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    • "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. "
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    • "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). "
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