RNA-mediated symmetry breaking enables singular olfactory receptor choice

Ariel D. Pourmorady, Elizaveta V. Bashkirova, Andrea M. Chiariello, Houda Belagzhal, Albana Kodra, Rachel Duffié, Jerome Kahiapo, Kevin Monahan, Joan Pulupa, Ira Schieren, Alexa Osterhoudt, Job Dekker, Mario Nicodemi and Stavros Lomvardas ()
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Ariel D. Pourmorady: Columbia University New York
Elizaveta V. Bashkirova: Columbia University New York
Andrea M. Chiariello: University of Naples, and INFN
Houda Belagzhal: University of Massachusetts Medical School
Albana Kodra: Vagelos College of Physicians and Surgeons
Rachel Duffié: Columbia University New York
Jerome Kahiapo: Rutgers School of Arts and Sciences, Robert Wood Johnson Medical School
Kevin Monahan: Rutgers School of Arts and Sciences, Robert Wood Johnson Medical School
Joan Pulupa: Columbia University New York
Ira Schieren: Columbia University New York
Alexa Osterhoudt: Columbia University New York
Job Dekker: University of Massachusetts Medical School
Mario Nicodemi: University of Naples, and INFN
Stavros Lomvardas: Columbia University New York

Nature, 2024, vol. 625, issue 7993, 181-188

Abstract: Abstract Olfactory receptor (OR) choice provides an extreme example of allelic competition for transcriptional dominance, where every olfactory neuron stably transcribes one of approximately 2,000 or more OR alleles1,2. OR gene choice is mediated by a multichromosomal enhancer hub that activates transcription at a single OR3,4, followed by OR-translation-dependent feedback that stabilizes this choice5,6. Here, using single-cell genomics, we show formation of many competing hubs with variable enhancer composition, only one of which retains euchromatic features and transcriptional competence. Furthermore, we provide evidence that OR transcription recruits enhancers and reinforces enhancer hub activity locally, whereas OR RNA inhibits transcription of competing ORs over distance, promoting transition to transcriptional singularity. Whereas OR transcription is sufficient to break the symmetry between equipotent enhancer hubs, OR translation stabilizes transcription at the prevailing hub, indicating that there may be sequential non-coding and coding mechanisms that are implemented by OR alleles for transcriptional prevalence. We propose that coding OR mRNAs possess non-coding functions that influence nuclear architecture, enhance their own transcription and inhibit transcription from their competitors, with generalizable implications for probabilistic cell fate decisions.

Date: 2024
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DOI: 10.1038/s41586-023-06845-4

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