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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. This ambitious experimental project not only will reveal molecular mechanisms that govern the nuclear organization of OR genes but also generally applicable principles and powerful technologies for the study of the mammalian nucleome in vivo.", "center_title": "NBC - Lomvardas", "display_title": "DECIPHERING NUCLEAR BODIES AND COMPARTMENTS THAT GOVERN SINGULAR OLFACTORY RECEPTOR EXPRESSION.", "@type": ["Award", "Item"], "name": "1U01DA040582-01", "pi": {"error": "no view permissions"}, "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, "files": [{"uuid": "4c239bb8-9cf9-456c-8716-c344a2d8aba0", "display_title": "4DNFIWISY4HJ.fastq.gz", "accession": "4DNFIWISY4HJ", "@type": ["FileFastq", "File", "Item"], "href": "/files-fastq/4DNFIWISY4HJ/@@download/4DNFIWISY4HJ.fastq.gz", "file_classification": "raw file", "file_type_detailed": "index reads (fastq)", "upload_key": "4c239bb8-9cf9-456c-8716-c344a2d8aba0/4DNFIWISY4HJ.fastq.gz", "status": "released", "file_type": 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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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(2022) PMID:35180380", "journal": "Cell", "authors": ["Zazhytska M", "Kodra A", "Hoagland DA", "Frere J", "Fullard JF", "Shayya H", "McArthur NG", "Moeller R", "Uhl S", "Omer AD", "Gottesman ME", "Firestein S", "Gong Q", "Canoll PD", "Goldman JE", "Roussos P", "tenOever BR", "Jonathan B Overdevest", "Lomvardas S"], "abstract": "SARS-CoV-2 infects less than 1% of cells in the human body, yet it can cause severe damage in a variety of organs. Thus, deciphering the non-cell-autonomous effects of SARS-CoV-2 infection is imperative for understanding the cellular and  molecular disruption it elicits. Neurological and cognitive defects are among the least understood symptoms of COVID-19 patients, with olfactory dysfunction being  their most common sensory deficit. Here, we show that both in humans and hamsters, SARS-CoV-2 infection causes widespread downregulation of olfactory receptors (ORs) and of their signaling components. This non-cell-autonomous effect is preceded by a dramatic reorganization of the neuronal nuclear architecture, which results in dissipation of genomic compartments harboring OR genes. Our data provide a potential mechanism by which SARS-CoV-2 infection alters the cellular morphology and the transcriptome of cells it cannot infect, offering insight to its systemic effects in olfaction and beyond.", "@id": "/publications/580ed421-772a-44ba-8650-77babd1da2b1/", "uuid": "580ed421-772a-44ba-8650-77babd1da2b1", "short_attribution": "Zazhytska M et al. (2022)", "title": "Non-cell-autonomous disruption of nuclear architecture as a potential cause of COVID-19-induced anosmia.", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, "publications_of_exp": [{"abstract": "SARS-CoV-2 infects less than 1% of cells in the human body, yet it can cause severe damage in a variety of organs. Thus, deciphering the non-cell-autonomous effects of SARS-CoV-2 infection is imperative for understanding the cellular and  molecular disruption it elicits. Neurological and cognitive defects are among the least understood symptoms of COVID-19 patients, with olfactory dysfunction being  their most common sensory deficit. Here, we show that both in humans and hamsters, SARS-CoV-2 infection causes widespread downregulation of olfactory receptors (ORs) and of their signaling components. This non-cell-autonomous effect is preceded by a dramatic reorganization of the neuronal nuclear architecture, which results in dissipation of genomic compartments harboring OR genes. Our data provide a potential mechanism by which SARS-CoV-2 infection alters the cellular morphology and the transcriptome of cells it cannot infect, offering insight to its systemic effects in olfaction and beyond.", "short_attribution": "Zazhytska M et al. (2022)", "ID": "PMID:35180380", "title": "Non-cell-autonomous disruption of nuclear architecture as a potential cause of COVID-19-induced anosmia.", "display_title": "Zazhytska M et al. (2022) PMID:35180380", "journal": "Cell", "status": "current", "authors": ["Zazhytska M", "Kodra A", "Hoagland DA", "Frere J", "Fullard JF", "Shayya H", "McArthur NG", "Moeller R", "Uhl S", "Omer AD", "Gottesman ME", "Firestein S", "Gong Q", "Canoll PD", "Goldman JE", "Roussos P", "tenOever BR", "Jonathan B Overdevest", "Lomvardas S"], "@id": "/publications/580ed421-772a-44ba-8650-77babd1da2b1/", "@type": ["Publication", "Item"], "date_published": "2022-03-17", "uuid": "580ed421-772a-44ba-8650-77babd1da2b1", "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": []}