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During OSN differentiation OR loci from multiple chromosomes converge into distinct, OSN-specific nuclear foci characterized by the hallmarks of constitutive heterochromatin. Absent from these unusual nuclear bodies is the OR allele that is transcriptionally active in each OSN, which typically resides on euchromatic nuclear compartments and is surrounded by numerous enhancer elements recruited from several chromosomes. This intricate network of interchromosomal interactions is responsible for both the robust transcription of the chosen OR allele and the complete silencing of the repressed ones. The extraordinary number of OR family members and the unprecedented extent of long-range genomic interactions that culminate to the remarkable organization of the OR nucleome, make the olfactory system ideal for they study of the molecular principles that organize the mammalian nuclear architecture in vivo. For a comprehensive interrogation of the OR nucleome, we assembled a multidisciplinary team seeking to combine novel genetic manipulations with a one of a kind imaging system, a state of the art proteomics facility, and innovative genomic analyses. With CRISPR, phiC31 integrase and in utero DNA electroporation we will tag OR loci and enhancers, making the OR subgenome accessible by three novel experimental strategies: High resolution imaging by correlated soft X-ray tomography and cryo- SIM; biochemical purification by sequence specific tagging with Halo and APEX followed by sophisticated mass spectrometry; and genomic analysis of long range interactions occurring during OSN differentiation using two different DNA modifying enzymes and single molecule real time sequencing. 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The file and the information about its provenance, i.e. which files were used as input to generate this output was provided by or done in collaboration with the lab that did the experiments to generate the raw data. 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Disruption in our ability to detect odors, or anosmia, has emerged as a hallmark symptom of infection with SARS-CoV-2, yet the mechanism behind this abrupt sensory deficit remains elusive. Here, using molecular evaluation of human olfactory epithelium (OE) from subjects succumbing to COVID-19 and a hamster model of SARS-CoV-2 infection, we discovered widespread downregulation of olfactory receptors (ORs) as well as key components of their signaling pathway. OR downregulation likely represents a non-cell autonomous effect, since SARS-CoV-2 detection in OSNs is extremely rare both in human and hamster OEs. A likely explanation for the reduction of OR transcription is the striking reorganization of nuclear architecture observed in the OSN lineage, which disrupts multi-chromosomal compartments regulating OR expression in humans and hamsters. Our experiments uncover a novel molecular mechanism by which a virus with a very selective tropism can elicit persistent transcriptional changes in cells that evade it, contributing to the severity of COVID-19.", "display_title": "Zazhytska M et al. (2021) doi:10.1101/2021.02.09.430314", "status": "current", "date_published": "2021-02-09", "@id": "/publications/14aefcd7-cec0-49b5-904f-851a9a1466f8/", "uuid": "14aefcd7-cec0-49b5-904f-851a9a1466f8", "ID": "doi:10.1101/2021.02.09.430314", "title": "Disruption of nuclear architecture as a cause of COVID-19 induced anosmia.", "short_attribution": "Zazhytska M et al. (2021)", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, "publications_of_exp": [{"short_attribution": "Zazhytska M et al. (2021)", "title": "Disruption of nuclear architecture as a cause of COVID-19 induced anosmia.", "uuid": "14aefcd7-cec0-49b5-904f-851a9a1466f8", "authors": ["Zazhytska M", "Kodra A", "Hoagland DA", "Fullard JF", "Shayya H", "Omer A", "Firestein S", "Gong Q", "Canoll PD", "Goldman JE", "Roussos P", "tenOever BR", "Overdevest JB", "Lomvardas S"], "journal": "bioRxiv : the preprint server for biology", "status": "current", "abstract": "Olfaction relies on a coordinated partnership between odorant flow and neuronal communication. Disruption in our ability to detect odors, or anosmia, has emerged as a hallmark symptom of infection with SARS-CoV-2, yet the mechanism behind this abrupt sensory deficit remains elusive. Here, using molecular evaluation of human olfactory epithelium (OE) from subjects succumbing to COVID-19 and a hamster model of SARS-CoV-2 infection, we discovered widespread downregulation of olfactory receptors (ORs) as well as key components of their signaling pathway. OR downregulation likely represents a non-cell autonomous effect, since SARS-CoV-2 detection in OSNs is extremely rare both in human and hamster OEs. A likely explanation for the reduction of OR transcription is the striking reorganization of nuclear architecture observed in the OSN lineage, which disrupts multi-chromosomal compartments regulating OR expression in humans and hamsters. Our experiments uncover a novel molecular mechanism by which a virus with a very selective tropism can elicit persistent transcriptional changes in cells that evade it, contributing to the severity of COVID-19.", "@id": "/publications/14aefcd7-cec0-49b5-904f-851a9a1466f8/", "ID": "doi:10.1101/2021.02.09.430314", "display_title": "Zazhytska M et al. (2021) doi:10.1101/2021.02.09.430314", "date_published": "2021-02-09", "@type": ["Publication", "Item"], "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}], "experiment_categorizer": {"field": "Default", "value": null}, "experiment_summary": "single cell RNA-seq on olfactory receptor cell", "@context": "/terms/", "aggregated-items": {"badges": []}, "validation-errors": []}