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A new published in Nature reveals how olfactory sensory neurons (OSNs) achieve extraordinary precision in selecting which genes to express.

The mechanism is surprising in that it involves solid-like molecular condensates that last for days, helping to solve a long-standing puzzle in genome organization.

The research, led by Prof. Stavros Lomvardas from Columbia University, addresses one of biology's most intriguing questions: How do olfactory sensory neurons in the nose manage to express only one olfactory receptor (OR) gene out of approximately 1,000 available options?

Each neuron must specialize in detecting specific odor molecules, and this precise selection process is known as singular OR choice. It is essential for our sense of smell.

Â鶹ÒùÔº spoke to Prof. Lomvardas about his motivation behind conducting this research.

"I am fascinated by the process of olfactory receptor choice and by the fact that these neurons deploy highly specific and extremely stable genomic interactions across chromosomes to achieve this goal," he explained.

The genome folding paradox

The study tackles what scientists call the genome folding paradox.

In cells, DNA contains both genes (which make proteins) and regulatory elements called enhancers (which control when genes are turned on or off).

These enhancers form selective, stable contacts with gene sequences located thousands of base pairs away while ignoring similar sequences nearby.

This challenges the conventional understanding of molecular interactions. Normally, proteins would bind to the nearest available site.

Prof. Lomvardas's previous work identified that OSNs create multi-chromosomal enhancer hubs. These are three-dimensional structures where regulatory enhancers from different chromosomes cluster together to activate a single OR gene. The biochemical basis for this process, however, remained elusive.

Unexpected solid behavior

The researchers focused on studying the behavior of two transcription factors (LHX2, EBF1) and an adapter protein (LDB1). Together, they regulate OR gene expression.

Using protein purification experiments and live cell imaging in cultured OSNs, the team initially expected to observe liquid-like condensates, similar to other biological phase separation systems. However, the experiments revealed something different.

"I always thought that this process would be guided by liquid phase transitions. This was my preconceived notion going into this project," admitted Prof. Lomvardas.

"However, the data that started to emerge from our experiments suggested otherwise. These condensates did not behave like liquid droplets but rather as solid aggregates."

The solid-like nucleoprotein condensates showed remarkable stability.

Unlike typical liquid droplets that merge upon contact and allow free molecular movement, these structures maintained their shape and exhibited no molecular exchange even after 10 minutes in fluorescence recovery (bleaching) experiments.

The results were so surprising that the researchers initially thought that it was an experimental artifact.

Composite motifs

To understand the mechanism behind this solid phase transition, the researchers conducted systematic sequence modification.

They identified that certain DNA sequences or composite motifs triggered the solid condensate formation. The precise pattern for the enhancers was an arrangement of LHX2 and EBF1 binding sites separated by exactly one base pair.

"We knew from previous experiments that the enhancers of olfactory receptor genes have a significant enrichment of a DNA motif that we termed 'composite' because it is a combination of two different DNA motifs separated by 1 DNA base," explained Prof. Lomvardas.

Therefore, when they noticed that solid condensates formed only with specific enhancers, the researchers immediately associated this with the presence of composite motifs.

This sequence specificity enables homophilic nucleoprotein interactions, a mechanism whereby protein complexes assembled on identical DNA motifs preferentially bind to each other while excluding complexes formed on different sequences.

To further understand the mechanism, the researchers studied 3D genome organization using olfactory tissues from mice. They found that the OR enhancers form "Greek Islands."

These Greek Islands represent highly specific, ultra-long-range interactions between enhancers on different chromosomes that contain composite motifs while excluding nearby enhancers lacking these sequences.

The condensates demonstrated resistance to chemical dissolution and maintained stability over days, explaining how neurons can establish permanent gene expression programs.

Beyond olfactory neurons

The findings suggest this mechanism may apply beyond olfaction to other cell types that require stable gene expression programs, particularly post-mitotic neurons.

"We are starting to realize that genomic interactions between DNA sequences that are megabases apart in the chromosome, or between chromosomes, are not unique to olfactory sensory neurons. Thus, similar biochemical principles must be deployed to orchestrate their assembly and promote their stability," said Prof. Lomvardas.

Going forward, the team plans to investigate the structural basis of these solid phase transitions and identify other biological systems that use similar principles.

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