Our noses have specialized “smelling cells” that control how we smell the world around us. These cells, called olfactory sensory neurons, help us decide if milk is spoiled or if there is a fire nearby. Each of these cells is covered with protein detectors, called olfactory receptors, that sense and transmit these smells to our brains. In humans, there are more than 400 different versions of these receptors that work together to help us recognize the trillions of smells in the world around us. The blueprints for these receptors are stored in the genes of our DNA. To make the receptors, the genes are read and transcribed into a carrier molecule known as RNA. The RNA is then translated into a different molecule called protein, which make up the olfactory receptors. 

Even though the DNA in each “smelling cell” contains the genes for hundreds of different versions of these receptors, each mature olfactory sensory neuron only produces one. Which version gets chosen is random, though work from NIH Common Fund 4D Nucleome (4DN) program researchers led by Dr. Stavros Lomvardas now sheds light on how this determination is made.

Early in their development, olfactory sensory neurons produce multiple versions of their receptors at once; a single version has yet to be chosen. Using mouse olfactory cells as a model, the group of researchers noticed that, as the cells developed, the receptors produced eventually all came from a single gene. By the time a cell finished maturing, only one out of the hundreds of different versions of the olfactory receptor was made. Additional factors within the DNA, called enhancers, help determine which of the olfactory receptor genes are used. The group’s experiments showed that, eventually, these enhancers formed a hub around one single active receptor gene. By focusing on a single gene, the enhancer hubs effectively turned off the multitude of other receptor genes. The group noticed that this choice was reinforced by an accumulation of the RNA that was transcribed from the active gene (called messenger RNA, or mRNA). Their experiments suggest that the mRNA inhibits activity of the other hundreds of competing receptor genes, though more studies are needed to decipher exactly why and how this process occurs. Dr. Lomvardas’s group speculated that the mRNA could be attracting another factor to help promote gene activity. They hypothesized that the mRNA may be influencing three-dimensional interactions between this additional factor, the active gene, and the enhancer hub, though they need to test this further. Such a function of mRNA has never been described before. This important work is another demonstration of how the spatial organization of genetic material in the nucleus, and changes to that organization, affect gene activity. These findings also contribute to our understanding of the role that such organization plays in cell development and function, which is a key goal of the NIH Common Fund’s 4DN program.

Reference

RNA-mediated symmetry breaking enables singular olfactory receptor choice. Pourmorady, AD, Bashkirova, EV, Chiariello, AM, Belagzhal, H, Kodra, A, Duffié, R, Kahiapo, J, Monahan, K, Pulupa, J, Schieren, I, Osterhoudt, A, Dekker, J, Nicodemi, M, & Lomvardas, S. Nature. 2024 Jan; 625(7993):181-188. doi: 10.1038/s41586-023-06845-4.