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SHM is essential for the fine-tuning of antibody affinity, the generation of B cells expressing high-affinity antibody, and the efficacy of many vaccines. Mistargeted SHM activities can lead to mutations and chromosomal translocations that contribute to the development of B cell lymphoma. Recent studies suggest that the three-dimensional (3D) organization of the genome regulates SHM targeting and mistargeting. However, it is largely unknown how the genome is spatially organized across multiple length scales in GC B cell development and lymphoma, and how 3D genome architecture mechanistically affects the targeting and mistargeting of SHM. Conventional approaches cannot address these questions in the primary GC tissue environment due to technical limitations. Here, we propose to apply a new method recently developed by our team, termed Multiplexed Imaging of Nucleome Architectures (MINA), to primary human tonsil tissue samples and malignant GC-derived human B cell lymphomas. We will investigate and test the association between SHM susceptibility and a variety of 3D nucleome architectures, including topologically associating domain (TAD) architecture, phase separation, and nuclear positioning of genomic regions relative to nuclear lamina, nucleoli, and nuclear pores. Through targeted genomic perturbations in human B cell lymphomas, we will test specific hypotheses linking SHM targeting elements to elevated chromatin looping interactions, TAD phase separation, nuclear pore proximity, and mutation vulnerability. Our study will significantly advance our understanding of the role of 3D genome architecture and nuclear organization in GC B cells undergoing SHM in both the developmental and tumorigenesis contexts. 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G", "Rajaei M", "Townsend JP", "Muzumdar MD", "Wang S"], "abstract": "Although three-dimensional (3D) genome structures are altered in cancer cells,  little is known about how these changes evolve and diversify during cancer  progression. Leveraging genome-wide chromatin tracing to visualize 3D genome  folding directly in tissues, we generated 3D genome cancer atlases of murine lung  and pancreatic adenocarcinoma. Our data reveal stereotypical, non-monotonic, and  stage-specific alterations in 3D genome folding heterogeneity, compaction, and  compartmentalization as cancers progress from normal to preinvasive and  ultimately to invasive tumors, discovering a potential structural bottleneck in  early tumor progression. Remarkably, 3D genome architectures distinguish  histologic cancer states in single cells, despite considerable cell-to-cell  heterogeneity. Gene-level analyses of evolutionary changes in 3D genome  compartmentalization not only showed compartment-associated genes are more  homogeneously regulated, but also elucidated prognostic and dependency genes in  lung adenocarcinoma and a previously unappreciated role for polycomb-group  protein Rnf2 in 3D genome regulation. Our results demonstrate the utility of  mapping the single-cell cancer 3D genome in tissues and illuminate its potential  to identify new diagnostic, prognostic, and therapeutic biomarkers in cancer.", "ID": "doi:10.1101/2023.07.23.550157", "uuid": "e83173f7-95e4-40ad-9748-e13b2a518fc6", "title": "Tracing the evolution of single-cell cancer 3D genomes: an atlas for cancer gene  discovery.", "display_title": "Liu M et al. (2024) doi:10.1101/2023.07.23.550157", "@type": ["Publication", "Item"], "short_attribution": "Liu M et al. (2024)", "journal": "bioRxiv : the preprint server for biology", "status": "current", "date_published": "2024-09-09", "@id": "/publications/e83173f7-95e4-40ad-9748-e13b2a518fc6/", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, "publications_of_exp": [{"status": "current", "journal": "bioRxiv : the preprint server for biology", "abstract": "Although three-dimensional (3D) genome structures are altered in cancer cells,  little is known about how these changes evolve and diversify during cancer  progression. Leveraging genome-wide chromatin tracing to visualize 3D genome  folding directly in tissues, we generated 3D genome cancer atlases of murine lung  and pancreatic adenocarcinoma. Our data reveal stereotypical, non-monotonic, and  stage-specific alterations in 3D genome folding heterogeneity, compaction, and  compartmentalization as cancers progress from normal to preinvasive and  ultimately to invasive tumors, discovering a potential structural bottleneck in  early tumor progression. Remarkably, 3D genome architectures distinguish  histologic cancer states in single cells, despite considerable cell-to-cell  heterogeneity. Gene-level analyses of evolutionary changes in 3D genome  compartmentalization not only showed compartment-associated genes are more  homogeneously regulated, but also elucidated prognostic and dependency genes in  lung adenocarcinoma and a previously unappreciated role for polycomb-group  protein Rnf2 in 3D genome regulation. Our results demonstrate the utility of  mapping the single-cell cancer 3D genome in tissues and illuminate its potential  to identify new diagnostic, prognostic, and therapeutic biomarkers in cancer.", "short_attribution": "Liu M et al. (2024)", "display_title": "Liu M et al. (2024) doi:10.1101/2023.07.23.550157", "uuid": "e83173f7-95e4-40ad-9748-e13b2a518fc6", "title": "Tracing the evolution of single-cell cancer 3D genomes: an atlas for cancer gene  discovery.", "authors": ["Liu M", "Jin S", "Agabiti SS", "Jensen TB", "Yang T", "Radda JSD", "Ruiz CF", "Baldissera G", "Rajaei M", "Townsend JP", "Muzumdar MD", "Wang S"], "@id": "/publications/e83173f7-95e4-40ad-9748-e13b2a518fc6/", "ID": "doi:10.1101/2023.07.23.550157", "date_published": "2024-09-09", "@type": ["Publication", "Item"], "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}], "experiment_categorizer": {"field": "Target", "value": "Total 473 TADs spanning between Chr1-Chr19 (mouse), Chromosomes", "combined": "Target: Total 473 TADs spanning between Chr1-Chr19 (mouse), Chromosomes"}, "experiment_summary": "multiplexed FISH on type II pneumocyte", "@context": "/terms/", "aggregated-items": {"badges": [{"parent": "/biosamples/4DNBSXG3UW34/", "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": []}