Call it a genomic nosegay. Unlike a floral nosegay, which releases scents, the genomic nosegay—a 3D spatial arrangement of olfactory receptor genes—helps us recognize them. Varied 3D arrangements are so effective that they allow us to distinguish one trillion different scents even though we have just 400 dedicated olfactory receptor genes.

The 3D arrangements, a recent discovery by Columbia University scientists, help explain how each of 10 million specialized olfactory neurons comes to express just one olfactory receptor gene, contributing to a random distribution of olfactory neuron types in the olfactory epithelium—a higher-order bouquet, if you will.

Underlying the tissue-level and cell-level arrangements are genome-level arrangements that incorporate chromosome-to-chromosome contacts. To catch the scent of these contacts, Columbia University scientists in the laboratory of Stavros Lomvardas, PhD, used Hi-C, a genome sequencing technique that captures chromosome conformations.

Detailed findings uncovered by the Columbia University team appeared January 9 in the journal Nature, in an article titled, “LHX2- and LDB1-mediated trans interactions regulate olfactory receptor choice.” The article describes how the genome coordinates the regulation of these genes in each neuron, thereby generating the biological diversity needed to detect the scents we experience.

“We’ve pinpointed a genomic mechanism by which a finite number of genes can ultimately help distinguish a seemingly near-infinite number of scents,” asserted Lomvardas. In particular, the scientists clarified the “one gene per neuron” rule.

Smell, also known as olfaction, is mind-bogglingly complex. The receptors in our noses must not only identify a scent, but also gauge how strong it is, scan our memories to determine whether it has been encountered before, and determine if it is pleasing or toxic.

Olfactory receptor neurons, specialized nerve cells that snake from the nose to the brain, make all this possible. And though each neuron contains the full suite of the 400 dedicated olfactory receptor genes, only one of these genes is active in each neuron. Adding to the confusion: the gene that is active appears randomly chosen, and differs from neuron to neuron.

This unusual pattern of gene activity, the “one gene per neuron” rule, and has long been a focus of study by scientists such as Lomvardas. Indeed, deciphering how each olfactory receptor neuron manages to activate only one of these genes—and how this process results in such a finely tuned sense of smell—remained mysterious for decades.

“In mice, olfactory receptor genes are scattered across the genome at about 60 different locations—on different chromosomes that are quite far apart from each other,” said Kevin Monahan, PhD, a postdoctoral research scientist in the Lomvardas lab and the paper’s co-first author. Mice have about 1,000 olfactory receptor genes, more than twice that of humans, potentially indicative of a superior sense of smell.

Traditionally, it has been thought that genes located on different chromosomes rarely, if ever, interacted with each other. By employing a new genomic sequencing technique called in situ Hi-C, Dr. Lomvardas and his team recently revealed that the chromosomes interacted much more frequently than expected.

“Chromatin conformation capture using in situ Hi-C on fluorescence-activated cell-sorted olfactory sensory neurons and their progenitors shows that olfactory receptor gene clusters from 18 chromosomes make specific and robust interchromosomal contacts that increase with differentiation of the cells,” wrote the Nature article’s authors. “These contacts are orchestrated by intergenic olfactory receptor enhancers, the ‘Greek islands’, which first contribute to the formation of olfactory receptor compartments and then form a multi-chromosomal super-enhancer that associates with the single active olfactory receptor gene.”

In situ Hi-C is revolutionary in large part because it allows us to map, in 3D, the entire genome inside a living cell,” said Adan Horta, PhD, a recently graduated doctoral candidate in the Lomvardas lab and the paper’s co-first author. “This gives us a snapshot of the genome at a particular point in time.”

“The Greek-island-bound transcription factor LHX2 and adaptor protein LDB1 regulate the assembly and maintenance of olfactory receptor compartments, Greek island hubs, and olfactory receptor transcription,” the article’s authors added, “providing mechanistic insights into and functional support for the role of trans interactions in gene expression.”

Snapshots taken by the researchers showed clusters of olfactory receptor genes, located on different chromosomes, physically moving toward each before choosing an olfactory receptor gene. Soon after these genes huddled together, another type of genetic element known as enhancers clustered in a separate 3D compartment. Enhancers are not themselves genes but regulate the activity of genes.

“We previously discovered a group of enhancers, we named the Greek Islands, located near the various olfactory receptor genes,” said Horta. “This work showed that these enhancers create hotspots of activity to regulate the “chosen” olfactory receptor gene.

The team also found that the protein Ldb1 plays a key role in this process. It holds the Greek Islands together, allowing them to switch on a specific olfactory receptor gene that then—as a team—interpret the particular scent at hand.

“These teams of genes endow the olfactory system with the ability to respond in diverse ways,” said Monahan. “The flexibility of this process could help to explain how we easily learn and remember new smells.”

Though specific to olfaction, the researchers’ findings could have implications for other areas of biology in which inter-chromosome interactions play a role.

“Interactions between chromosomes may be the culprit for shifts in the genome—called genomic translocations—that are known to cause cancer,” said Lomvardas. “Could the activities of other cells be shaped by the three-dimensional changes we see in olfactory receptor neurons? This is an open question that we hope to explore.”

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