# Olfactory receptor mRNAs as lncRNAs that regulate genomic interactions

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $480,534

## Abstract

Abstract
The monogenic, monoallelic, and seemingly stochastic transcriptional choice of one out of > 1000 olfactory
receptor (OR) genes remained elusive for decades after the discovery of the largest mammalian gene family.
However, in the past few years we obtained significant understanding on the molecular underpinnings of this
enigmatic gene regulatory process. Specifically, we showed that OR gene clusters become heterochromatic at
the early stages of olfactory sensory neuron (OSN) differentiation and then they aggregate in distinct nuclear
compartments that assure their stable repression. As a result of this interchromosomal convergence, intergenic
OR enhancers (known as Greek Islands) that are found in most OR gene clusters come in close nuclear
proximity and form a multi-chromosomal super-enhancer that in each OSN associates with the transcriptionally
active OR allele. The formation of the Greek Island hub is dependent upon the recruitment of the adaptor
protein Ldb1, which is essential for the stable interchromosomal interactions between Greek Islands and for
OR transcription. This intricate network of activating and repressive interchromosomal interactions, together
with a feedback signal elicited by the expression of the chosen OR, likely generate the regulatory framework
for transcriptional singularity. However, what remains unknown is the process by which an OR allele is
recruited to the Greek Island hub and the mechanism that assures that only one OR allele will remain stably
associated with a multi-chromosomal structure that contains numerous enhancer elements. Our preliminary
data suggest that developmentally transient OR transcription and production of nascent OR mRNAs contribute
to the recruitment of an OR allele to the Greek Island hub and to OR gene choice. Thus, we propose genetic
experiments that will determine which sequences of the sense OR mRNA are required and sufficient for
recruitment of trans OR enhancers, what proteins recognized the nascent OR mRNA and what contribution
these proteins have to the assembly of a multi-enhancer/OR complex. These experiments not only will shed
light to the enigmatic process of OR gene choice, but will also provide general molecular principles for the
mechanisms that mediate genomic compartmentalization during cellular differentiation.

## Key facts

- **NIH application ID:** 10112224
- **Project number:** 5R01DC018744-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Stavros Lomvardas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $480,534
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112224

## Citation

> US National Institutes of Health, RePORTER application 10112224, Olfactory receptor mRNAs as lncRNAs that regulate genomic interactions (5R01DC018744-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10112224. Licensed CC0.

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