Theses Doctoral

The Role of Chromatin in Olfaction

Kodra, Albana Lavinia

The organization of the genome of olfactory sensory neurons (OSN) plays a crucial role in the singular choice of one olfactory receptor (OR) allele out of thousands. For each OSN, the identity of the expressed OR determines the spectrum of chemicals that it responds and its connectivity to the brain. In situ HiC experiments suggest that OSN differentiation coincides with OR gene compartmentalization followed by generation of sub compartment occupied by intergenic OR enhancers and the transcriptionally chosen OR allele, in a process mediated by LIM-binding protein Ldb1 and two transcription factors Lhx2 and Ebf.

To investigate how these interactions regulates robust transcription of one singular OR allele, and ensure diversity in the olfactory epithelium, we use single cell high resolution imaging approaches combined with high-throughput Oligopaint labeling of OR enhancers and their flanking regions. We confirm that interchromosomal enhancer convergence increases with OSNs differentiation in a Ldb1 dependent fashion and that OR gene clusters converge into a small number of heterochromatic foci.

Interestingly, the multi-enhancer hub only partially colocalizes with its flanking heterochromatic regions, suggesting drastic spatial rearrangements of these regions. We also observe that the multi-chromosomal enhancer hub colocalizes with the single active OR allele, confirming that singular OR gene activation is mediated by its assembly over a stochastically chosen OR allele.

Furthermore, using 3D single-molecule localization microscope we observe that Lhx2 and Ebf, although ubiquitously expressed, are highly concentrated in one specific region in close proximity to the heterochromatic nucleus suggesting the presence of a protein-protein interaction network hub.

SARS-CoV-2 induces non-cell autonomous effects in olfactory epithelium that disrupts nuclear architecture and downregulates olfactory receptor expression in olfactory sensory neurons. Downregulation of odor detection pathways may explain COVID-19-induced anosmia SARS-CoV-2-mediated disruption of nuclear architecture may impair odor detection SARS- CoV-2-mediated nuclear reorganization is non-cell autonomous.


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More About This Work

Academic Units
Genetics and Development
Thesis Advisors
Lomvardas, Stavros
Johnston, Laura
Ph.D., Columbia University
Published Here
May 10, 2023