Gene Regulation and Chromatin Structure of Mammalian Olfactory Receptors

Abstract

Mammals sense odors by expressing the gene family of olfactory receptors (ORs). Despite the massive family size — around 1,000 OR genes in the mouse genome and 400 in human, each sensory neuron randomly expresses one, and only one, OR. This phenomenon, termed the “one-neuron-one-receptor” rule, underlies both odor sensing in the nose and the formation of an odor map in the brain. However, it remains a mystery how this rule is established. Combining theoretical modeling, single-cell transcriptomics, spatial transcriptomics, and single-cell 3D genome structures, we investigated the regulation of OR genes during neuronal development. We identified a fundamental kinetic constraint in a recent model of epigenetic OR regulation, uncovered a surprising phenomenon of transient multi-OR expression in immature neurons, created by far the most comprehensive spatial map of mouse ORs in the nose, and revealed for the first time 3D genome structures of single diploid human and mouse cells including olfactory sensory neurons. Our interdisciplinary approach provided valuable insights into the molecular mechanism behind the “one-neuron-one-receptor” rule of OR expression; and our methods could be widely applicable to other systems where gene regulation and chromatin structure underlie important physiological functions.