# Deciphering the molecular principles of olfactory receptor gene choice

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $388,015

## Abstract

Research Summary
The molecular mechanisms by which a finite genome generates an almost infinite ensemble of cellular
identities are poorly understood. The mammalian olfactory epithelium provides an extreme example of cellular
heterogeneity in which the functional identity of each olfactory sensory neuron (OSN) is determined by the
identity of the olfactory receptor (OR) it expresses. In the mouse each OSN expresses only one out of more
than a thousand OR genes in seemingly stochastic and monoallelic fashion. Although some of the regulatory
layers governing this remarkable process were recently elucidated, important questions remain open. For
example, we previously showed that the transcriptionally active OR allele associates with an intricate
interchromosomal hub that contains intergenic OR enhancers from many chromosomes. Here, we seek to
elucidate the molecular signatures that distinguish intergenic OR enhancers and promoters from the rest of the
genome, allowing the formation of specific genomic interactions that culminate in robust OR transcription.
Using ATAC-seq and ChIP-seq approaches in FACsorted olfactory neurons, we identified a novel genetic
signature that is highly enriched on intergenic OR enhancers and likely promotes the cooperative binding of
transcription factors (TFs) that occupy most OR enhancers. Cooperative TF binding on this novel motif likely
permits the synergistic recruitment of two distinct types of adaptor proteins to intergenic OR enhancers,
creating a unique molecular surface that may dictate the specificity on enhancer-enhancer and enhancer-
promoter interactions in the OR subgenome. We therefore propose genetic experiments that will test these
predictions and will elucidate the specificity by which intergenic OR enhancers become recognized by TFs, the
specificity by which OR enhancers interact with each other and the specificity by which they recruit OR
promoters. Because the proteins we propose to investigate are expressed in many neuronal tissues, the
regulatory principles that will produced by these studies are likely to impact our general understanding of the
combinatorial control of neuronal specification.

## Key facts

- **NIH application ID:** 9952348
- **Project number:** 5R01DC015451-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Stavros Lomvardas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,015
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952348

## Citation

> US National Institutes of Health, RePORTER application 9952348, Deciphering the molecular principles of olfactory receptor gene choice (5R01DC015451-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9952348. Licensed CC0.

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