# Principles of zonal olfactory receptor gene expression

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $458,789

## 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 how this seemingly stochastic process
operates under deterministic restrictions related to the spatial location of the OSN along the dorso-ventral and
apico-basal axes of the MOE. These restrictions, known as zonal pattern of OR expression, restrict the
expression of each OR gene in one of five zones of expression. Here we identified putative mechanisms of
zonal restriction, by uncovering the molecular mechanisms that enable only zone 5 ORs to be expressed in
zone 5. We show that transcription factors of the NFI family enable the transcriptional activation of zone 5 ORs,
by mediating the recruitment of these ORs to the interchromosomal OR compartment. Moreover, we show that
the repressive histone modification H3K79me3 prevents the expression of out of zone ORs, possibly under the
control of NFI factors, as well. We propose experiments that will decipher which NFI factors are required and
sufficient for specification of zone 5 transcription programs, and experiment that will determine how NFI
proteins accomplish these zonal restrictions. Our experiments will reveal novel mechanisms of regulation of
nuclear architecture, and will uncover generally applicable principles for the regulation of developmental
patterning.

## Key facts

- **NIH application ID:** 10109110
- **Project number:** 5R01DC018745-02
- **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:** $458,789
- **Award type:** 5
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109110

## Citation

> US National Institutes of Health, RePORTER application 10109110, Principles of zonal olfactory receptor gene expression (5R01DC018745-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10109110. Licensed CC0.

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