An Epigenetic Trap Stabilizes Singular Olfactory Receptor Expression

Abstract

Summary 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 co-activator, LSD1 is necessary for de-silencing and initiating OR transcription, but as a transcriptional co-repressor, 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.

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

“…With this marker, all OR genes are deeply repressed in nuclear aggregates before activation (9). The existence of negative feedback was also confirmed recently: Once a choice of ORs is made, the histone demethylase Lsd1 (also known as Aof2 or Kdm1a) will be transcriptionally repressed by OR expression (10,11). Lsd1 down-regulation will prevent further activation and freeze the system after the choice because this enzyme is essential for OR activation.…”

“…repressive H3K9me3 marker-involves two consecutive steps: H3K9me3-toH3K9me2 demethylation by an unidentified demethylase (off→intermediate, with a rate k me3→me2 ), and then H3K9me2 demethylation by Lsd1 (intermediate→on, with a rate k on ) (10,12,13). Notice that here we focus on the activator role of Lsd1; its second role as a repressor is discussed in the last subsection of Results.…”

“…Notice that here we focus on the activator role of Lsd1; its second role as a repressor is discussed in the last subsection of Results. Once fully activated, OR expression will transcriptionally down-regulate Lsd1 via a recently identified cascade (OR activates the adenylate cyclase Adcy3, which in turn represses Lsd1) (10,11), whose response time is denoted Δt. If the feedback is instant, namely, Δt = 0, singularity will be perfect; however, this is not physiological because Lsd1 depletion takes time (thus Δt > 0).…”

“…Although these studies hypothesized that a slow activation may help singularity (8)(9)(10), it is not obvious at a quantitative level whether this scheme is feasible. The critical assessment is whether a slow kinetics can really generate singularity and, if so, what the requirements are for the kinetic parameters.…”

Genetic variability of ESAG6/7 gene Trypanosoma evansi

“…The control of antigenic variation was influenced by two main things: the virulence and avoiding strategy of immune response, and expression of mono-allele gene (Lyons et al 2013). Glover et al (2013) described that trypanosome used about one-third of nucleus gene and all sub telomere for activating and inactivating the VSG gene and the sequence related to the VSG.…”