title: Rare event of histone demethylation can initiate singular gene expression of olfactory receptors.
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.
authors.forename: Longzhi
authors.initials: L
authors.lastname: Tan
authors.forename: Chenghang
authors.initials: C
authors.lastname: Zong
authors.forename: X Sunney
authors.initials: XS
authors.lastname: Xie
mesh_terms: D000818:Animals; D044127:Epigenesis, Genetic / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D056466:Histone Demethylases / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008959:Models, Neurological; D018034:Olfactory Receptor Neurons / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D018035:Receptors, Odorant / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D018035:Receptors, Odorant; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D010089:Oxidoreductases, N-Demethylating