Epigenetic programming of stochastic olfactory receptor choice

Abstract

The mammalian sense of smell relies upon a vast array of receptor proteins to detect odorant compounds present in the environment. The proper deployment of these receptor proteins in olfactory sensory neurons is orchestrated by a suite of epigenetic processes that remodel the olfactory genes in differentiating neuronal progenitors. The goal of this review is to elucidate the central role of gene regulatory processes acting in neuronal progenitors of olfactory sensory neurons that lead to a singular expression of an odorant receptor in mature olfactory sensory neurons. We begin by describing the principal features of odorant receptor gene expression in mature olfactory sensory neurons. Next, we delineate our current understanding of how these features emerge from multiple gene regulatory mechanisms acting in neuronal progenitors. Finally, we close by discussing the key gaps in our understanding of how these regulatory mechanisms work and how they interact with each other over the course of differentiation.

Keywords: chemosensory neurons; chromatin; gene expression; heterochromatin; olfaction; olfactory receptors; vomeronasal organ.

Figure 1:. Fate Restriction of Olfactory Sensory Neurons leading to stochastically chosen Olfactory Receptor gene

Olfactory sensory neurons go through several stages of differentiation to reach a mature olfactory sensory neuron state. A. Anatomy and classification of the different types of odorant receptors based on where they are present, including total numbers of each receptor type. Type I, Type II and Formyl Peptide Receptors (FPRs) are present in the Vomeronasal Organ. Trace Amine-Associated Receptor, Class I, Class II and MS4A receptors are present in the main olfactory epithelium and accessory organs like septum and Gruenberg ganglion. B. During differentiation, two levels of cell-fate determination occur. Global Basal Cells (GBCs) or Horizontal Basal Cells (HBCs) are stem cells that can give rise to intermediate neuronal progentiors (INP) and then immature OSN (iOSN) stage. They are restricted into either a class I or class II or TAAR type of OSN, followed by stochastic expression of chosen olfactory receptor (OR). Class II OSNs are further estricted into zonal identities (Zone 1–5) that correspond to specific anatomical regions of the tissue.

Figure 2:. Location of class I and class II OR and TAAR genes across mouse genome

Class I OR genes (blue) are located in one cluster in chromosome 7 and TAAR gene cluster (purple) is in chromosome 10. Meanwhile, class II OR gene clusters (red) are spread across multiple chromosomes.

Figure 3:. Model of Olfactory Receptor gene arrangement

Inactive Olfactory Receptor (OR) genes rearrange themselves in 3D space during the course of differentiation from Horizontal Basal Cells (HBC) to Immediate Neuronal Progenitors (INPs) to Mature Olfactory Sensory Neurons (mOSNs). The active OR is looped out of the constitutively silenced heterochromatin compartment and associates with the enhancer hub so that the single chosen OR is ready for transcription in mOSNs.

Figure 4:. Summary of epigenetic events during olfactory sensory neuron differentiation

Multiple key developmental processes occur in the immediate neuronal progenitors (INP) and immature olfactory sensory neuron (iOSN) stages that lead to single OR allele expression in mature OSNs (mOSNs).