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Recent years have seen a rapid expansion of the understanding of many of the basic features that define how genomes are organized in space inside of cells, including the identification of features such as A/B compartments, Topologically Associated Domains, and chromatin loops. Furthermore, there is evidence that mutations that alter 3D genome organization can contribute to human disease. This is most evident for a class of mutations known as structural variants, which includes translocations, inversions, tandem duplications, and deletions. When these mutations disrupt sequence features that are critical for 3D genome structure, such as the boundaries between Topologically Associating Domains, this can lead to enhancer-promoter rewiring, changes in gene expression, and phenotypic consequences. Such effects have been observed both in the context of germline structural variants that contribute to syndromic disorders of development as well as somatic structural variants that can lead to cancer. While it has become clear that structural variants can alter 3D genome organization and gene expression, more recent studies that comprehensively examined structural variants and gene expression indicate their relationship is considerably more complex. Specifically, in only a minority of instances do structural variants lead to changes in expression of neighboring genes. Therefore, why structural variants can have dramatic consequences on 3D genome structure and gene expression in some contexts but not others is currently unclear. This proposal will investigate the relationship between structural variants, 3D genome organization, and gene expression in cancer genomes with the goal of understanding where and when structural variants will actually lead to changes in gene expression that may contribute to oncogenesis. Specific aim 1 will test whether only specific sets genes are sensitive to structural variant induced changes in enhancer-promoter communication by examining changes in 3D genome structure and gene expression in haplotype resolved human tumor samples. Specific aim 2 will use CRISPR/Cas9 genome engineering to evaluate the effects of structural variant partner regions on induction of oncogene expression. Specific aim 3 will assess the role of intra-tumor heterogeneity on the effects of structural variants on 3D genome structure by using novel multi-omic methods for profiling DNA methylation and 3D genome structure simultaneously within single cells derived from patient tumor samples. Successful completion of these aims will result in a deeper understanding of the relationship between structural variation, 3D genome organization, and gene regulation in the context of cancer genomes. 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Here, we utilized acute depletion of NIPBL to characterize the role of cohesin-mediated loop extrusion in vivo. Using this approach, we found that many chromatin loops are rapidly diminished upon loss of NIBPL, consistent with recent single locus imaging studies showing that chromatin loops are transient. However, we also identified cohesin-dependent chromatin loops that are associated with distinct chromatin states and may be \"long-lived\", given that they require NIPBL for their establishment upon mitotic exit, but are persistent when NIPBL is depleted from interphase cells. In addition to the reformation of 3D genome structures, mitotic exit coincides with widespread transcriptional activation. We found that NIPBL is essential for establishing the expression of lineage-defining genes during the M-G1 transition but has diminished impact on the steady-state maintenance of their expression. At genes sensitive to its depletion, NIPBL supports a unique local genome organization defined by greater spatial proximity to nearby super-enhancers and weaker transcription start site insulation of genomic contacts. Overall, we show that NIPBL-mediated loop extrusion is critical to genome organization and transcription regulation in vivo.", "uuid": "aa466825-4805-4255-a852-46e27a7bd8ed", "short_attribution": "Popay TM et al. (2024)", "journal": "bioRxiv", "authors": ["Popay TM", "Pant A", "Munting F", "Black ME", "Haghani N", "Dixon J"], "ID": "doi:10.1101/2024.10.02.616323", "@id": "/publications/aa466825-4805-4255-a852-46e27a7bd8ed/", "date_published": "2024-10-02", "display_title": "Popay TM et al. (2024) doi:10.1101/2024.10.02.616323", "title": "Genome-wide in vivo dynamics of cohesin-mediated loop extrusion and its role in transcription activation", "status": "current", "@type": ["Publication", "Item"], "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, "publications_of_exp": [{"display_title": "Popay TM et al. (2024) doi:10.1101/2024.10.02.616323", "authors": ["Popay TM", "Pant A", "Munting F", "Black ME", "Haghani N", "Dixon J"], "@type": ["Publication", "Item"], "date_published": "2024-10-02", "journal": "bioRxiv", "short_attribution": "Popay TM et al. (2024)", "ID": "doi:10.1101/2024.10.02.616323", "uuid": "aa466825-4805-4255-a852-46e27a7bd8ed", "abstract": "The organization of the genome in three-dimensional space is highly dynamic, yet how these dynamics are regulated and the role they play in genome function is poorly understood. Here, we utilized acute depletion of NIPBL to characterize the role of cohesin-mediated loop extrusion in vivo. Using this approach, we found that many chromatin loops are rapidly diminished upon loss of NIBPL, consistent with recent single locus imaging studies showing that chromatin loops are transient. However, we also identified cohesin-dependent chromatin loops that are associated with distinct chromatin states and may be \"long-lived\", given that they require NIPBL for their establishment upon mitotic exit, but are persistent when NIPBL is depleted from interphase cells. In addition to the reformation of 3D genome structures, mitotic exit coincides with widespread transcriptional activation. We found that NIPBL is essential for establishing the expression of lineage-defining genes during the M-G1 transition but has diminished impact on the steady-state maintenance of their expression. At genes sensitive to its depletion, NIPBL supports a unique local genome organization defined by greater spatial proximity to nearby super-enhancers and weaker transcription start site insulation of genomic contacts. Overall, we show that NIPBL-mediated loop extrusion is critical to genome organization and transcription regulation in vivo.", "status": "current", "@id": "/publications/aa466825-4805-4255-a852-46e27a7bd8ed/", "title": "Genome-wide in vivo dynamics of cohesin-mediated loop extrusion and its role in transcription activation", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}], "experiment_categorizer": {"field": "Enzyme", "value": "Arima - A1, A2", "combined": "Enzyme: Arima - A1, A2"}, "experiment_summary": "in situ Hi-C on dTAG-NIPBL hTERT-RPE-1 - clone D7 with Arima - A1, A2", "@context": "/terms/", "aggregated-items": {"badges": [{"parent": "/biosamples/4DNBSUUQE7F2/", "embedded_path": "biosample.badges", "item": {"messages": ["Biosample missing Cell Culture Details"], "badge": {"commendation": null, "warning": "Biosample Metadata Incomplete", "uuid": "2b2cc7ff-b7a8-4138-9a6c-22884fc71690", "@id": "/badges/biosample-metadata-incomplete/", "badge_icon": "/static/img/badges/biosample-icon.svg", "description": "Biosample is missing metadata information required as part of the standards implemented by the 4DN Samples working group."}}}]}, "validation-errors": []}