{"lab": {"title": "Siyuan Wang, YALE", "status": "current", "@type": ["Lab", "Item"], "uuid": "7f49b420-d2ae-4de4-820a-21403dc0749f", "display_title": "Siyuan Wang, YALE", "@id": "/labs/siyuan-wang-lab/", "correspondence": [{"contact_email": "c2l5dWFuLndhbmdAeWFsZS5lZHU=", "@id": "/users/774c29b8-db1e-48bc-9669-a3e380f435c2/", "display_title": "Siyuan Wang"}], "pi": {"error": "no view permissions"}, "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin", "role.lab_submitter", "submits_for.7f49b420-d2ae-4de4-820a-21403dc0749f"]}}, "award": {"uuid": "f959fce7-bd94-4a8d-961d-8c72a4eaa1ad", "project": "4DN", "description": "OFHHD: During the humoral immune response, somatic hypermutation (SHM) introduces point mutations in rearranged immunoglobulin (Ig) genes of activated germinal center (GC) B cells. 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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"microscopy_technique": "Widefield", "@id": "/experiments-mic/4DNEXOAWHK2K/", "@type": ["ExperimentMic", "Experiment", "Item"], "uuid": "b8096c26-7041-4478-af10-e927995fa1fa", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}, "display_title": "multiplexed FISH on H7-hESC - 4DNEXOAWHK2K", "external_references": [], "experiment_sets": [{"experimentset_type": "replicate", "status": "released", "@id": "/experiment-set-replicates/4DNESA93WQSO/", "accession": "4DNESA93WQSO", "uuid": "854b25c2-6b5e-4792-9405-5411958dde0c", "@type": ["ExperimentSetReplicate", "ExperimentSet", "Item"], "display_title": "4DNESA93WQSO", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}], "produced_in_pub": {"authors": ["Patterson B", "Yang B", "Tanaka Y", "Kim KY", "Cakir B", "Xiang Y", "Kim J", "Wang S", "Park IH"], "short_attribution": "Patterson B et al. (2023)", "status": "current", "uuid": "2fab6d6e-0c82-4ce4-872d-9e69af521936", "@type": ["Publication", "Item"], "ID": "PMID:37540754", "display_title": "Patterson B et al. (2023) PMID:37540754", "abstract": "Three-dimensional (3D) genomics shows immense promise for studying X chromosome  inactivation (XCI) by interrogating changes to the X chromosomes' 3D states.  Here, we sought to characterize the 3D state of the X chromosome in naive and  primed human pluripotent stem cells (hPSCs). Using chromatin tracing, we analyzed  X chromosome folding conformations in these cells with megabase genomic  resolution. X chromosomes in female naive hPSCs exhibit folding conformations  similar to the active X chromosome (Xa) and the inactive X chromosome (Xi) in  somatic cells. However, naive X chromosomes do not exhibit the chromatin  compaction typically associated with these somatic X chromosome states. In H7  naive human embryonic stem cells, XIST accumulation observed on damaged X  chromosomes demonstrates the potential for naive hPSCs to activate XCI-related  mechanisms. Overall, our findings provide insight into the X chromosome status of  naive hPSCs with a single-chromosome resolution and are critical in understanding  the unique epigenetic regulation in early embryonic cells.", "title": "Female naive human pluripotent stem cells carry X chromosomes with Xa-like and  Xi-like folding conformations.", "journal": "Science advances", "@id": "/publications/2fab6d6e-0c82-4ce4-872d-9e69af521936/", "date_published": "2023-08-04", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, "publications_of_exp": [{"abstract": "Three-dimensional (3D) genomics shows immense promise for studying X chromosome  inactivation (XCI) by interrogating changes to the X chromosomes' 3D states.  Here, we sought to characterize the 3D state of the X chromosome in naive and  primed human pluripotent stem cells (hPSCs). Using chromatin tracing, we analyzed  X chromosome folding conformations in these cells with megabase genomic  resolution. X chromosomes in female naive hPSCs exhibit folding conformations  similar to the active X chromosome (Xa) and the inactive X chromosome (Xi) in  somatic cells. However, naive X chromosomes do not exhibit the chromatin  compaction typically associated with these somatic X chromosome states. In H7  naive human embryonic stem cells, XIST accumulation observed on damaged X  chromosomes demonstrates the potential for naive hPSCs to activate XCI-related  mechanisms. Overall, our findings provide insight into the X chromosome status of  naive hPSCs with a single-chromosome resolution and are critical in understanding  the unique epigenetic regulation in early embryonic cells.", "@type": ["Publication", "Item"], "ID": "PMID:37540754", "authors": ["Patterson B", "Yang B", "Tanaka Y", "Kim KY", "Cakir B", "Xiang Y", "Kim J", "Wang S", "Park IH"], "@id": "/publications/2fab6d6e-0c82-4ce4-872d-9e69af521936/", "short_attribution": "Patterson B et al. (2023)", "display_title": "Patterson B et al. (2023) PMID:37540754", "title": "Female naive human pluripotent stem cells carry X chromosomes with Xa-like and  Xi-like folding conformations.", "status": "current", "uuid": "2fab6d6e-0c82-4ce4-872d-9e69af521936", "date_published": "2023-08-04", "journal": "Science advances", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}], "experiment_categorizer": {"field": "Target", "value": "20 TADs chrX (1-20), 20 TADs chrX (21-40), XIST transcript", "combined": "Target: 20 TADs chrX (1-20), 20 TADs chrX (21-40), XIST transcript"}, "experiment_summary": "multiplexed FISH on H7-hESC", "@context": "/terms/", "aggregated-items": {"badges": [{"parent": "/biosamples/4DNBSDERJVJP/", "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": []}