# Interrogating genome folding trajectories in health and disease

> **NIH NIH U01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $622,658

## Abstract

Project Summary
Detection and identification of the astronomical number of volatile chemicals that we perceive as odors
depends upon the monogenic and monoallelic expression of olfactory receptor (OR) genes in olfactory sensory
neurons (OSNs). An intricate network of OSN-specific interchromosomal interactions coordinates the
transcriptional activation of only 1 OR allele out of >2000 OR alleles distributed across 18 different
chromosomes. Genomic interactions between silent OR genes assemble heterochromatic multi-chromosomal
compartments that keep OR genes transcriptionally inactive, whereas genomic interactions between intergenic
OR enhancers result in a multi-chromosomal enhancer hub that activates singular OR transcription. Here, we
propose to combine Dip-C, a variation of single cell HiC, with viral-based cell tagging technologies, towards the
identification of genome folding intermediates across OSN differentiation lineages. This “cradle to crate”
genomic analysis will follow individual OSN progenitors and their barcoded progeny, allowing a complete
cartography of genomic interactions made by every OR allele en route to transcriptional activation. Single
molecule DNA FISH experiments will complement the proposed genomic studies, providing high resolution
insight to the genomic choreography that orchestrates singular OR gene choice during development. Finally,
we seek to explore how the trajectories of OSN genomic folding become altered and eventually disrupted in a
humanized model for Alzheimer’s disease (AD). Olfactory dysfunction, hyposmia, and anosmia constitute well-
established prodromal symptoms of AD, but the molecular etiology of this intriguing connection is not known.
Using a humanized model for AD we discovered that interchromosomal OR compartments dissipate prior to
the onset of neurodegeneration, resulting in strong downregulation of OR transcription. Thus, we propose to
apply our single cell interrogation of genome folding transition in the context of AD and to establish the
baseline of nuclear architecture in human OSNs. Deciphering how OR compartments assemble in health, and
how they become disrupted in disease, may provide the basis for novel prognostic and diagnostic tools for AD,
and molecular assays for in vivo screening of AD therapeutics.

## Key facts

- **NIH application ID:** 10911096
- **Project number:** 5U01DA052783-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Stavros Lomvardas
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $622,658
- **Award type:** 5
- **Project period:** 2020-09-30 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911096

## Citation

> US National Institutes of Health, RePORTER application 10911096, Interrogating genome folding trajectories in health and disease (5U01DA052783-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10911096. Licensed CC0.

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