Rare event of histone demethylation can initiate singular gene expression of olfactory receptors

Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2013; 110(52). DOI: 10.1073/pnas.1321511111
Source: PubMed

ABSTRACT Mammals sense odors through the gene family of olfactory receptors (ORs). Despite the enormous number of OR genes (∼1,400 in mouse), each olfactory sensory neuron expresses one, and only one, of them. In neurobiology, it remains a long-standing mystery how this singularity can be achieved despite intrinsic stochasticity of gene expression. Recent experiments showed an epigenetic mechanism for maintaining singular OR expression: Once any ORs are activated, their expression inhibits further OR activation by down-regulating a histone demethylase Lsd1 (also known as Aof2 or Kdm1a), an enzyme required for the removal of the repressive histone marker H3K9me3 on OR genes. However, it remains unclear at a quantitative level how singularity can be initiated in the first place. In particular, does a simple activation/feedback scheme suffice to generate singularity? Here we show theoretically that rare events of histone demethylation can indeed produce robust singularity by separating two timescales: slow OR activation by stepwise H3K9me3 demethylation, and fast feedback to turn off Lsd1. Given a typical 1-h response of transcriptional feedback, to achieve the observed extent of singularity (only 2% of neurons express more than one ORs), we predict that OR activation must be as slow as 5-10 d-a timescale compatible with experiments. Our model further suggests H3K9me3-to-H3K9me2 demethylation as an additional rate-limiting step responsible for OR singularity. Our conclusions may be generally applicable to other systems where monoallelic expression is desired, and provide guidelines for the design of a synthetic system of singular expression.

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    • "Thus, for most ORs, H3K9 demethylation is necessary, but not sufficient, for expression at high cellular levels. Although recent theoretical calculations support that a slow demethylation process combined with a fast feedback can explain singular OR expression (Tan et al., 2013), our experimental findings suggest that an additional regulatory layer may also contribute to the singularity of OR choice. Were the absence of H3K9 methylation sufficient for robust OR transcription, then most G9a/GLP KO OSNs should express multiple ORs at high levels. "
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