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In this proposal, we aim to develop a suite of novel technologies for comprehensive structural and dynamic analyses of genomes, in two aspects: (1) the spatial interactions and higher-order organization of genomic DNA and (2) the functional organization of protein complexes driving the 3D folding of genomes. The new computational and experimental methods proposed herein integrate multiple experimental inputs and generate physical higher-order models of the 3D nuclear genome organization. Analysis of these models will yield new insights into the principles and structure/functions relationships of the genome's 3D organization in space and time. We have the following aims: (1) Develop technologies for mapping the relative spatial positions of genomic DNA in the nucleus: our focus will be on the three major technical barriers faced by all current mapping technologies, namely inefficient and potentially biased data acquisition, lack of temporal resolution, and missing higher-order contact information. (2) Develop technologies for deciphering the \"Protein Code\" of 3D genome organizations: we will employ a proven pipeline for the isolation of native protein complexes, but extensively optimized for the purpose of reading out the chromatin interactome surrounding each particular chromatin interacting region. (3) Develop technologies for modeling and analysis of 3D genome structures: we will develop an integrated platform for population-based modeling of 3D genome structures, and develop a series of computational tools to perform structure-function mapping on the 3D genomes. 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["group.admin"]}, "display_title": "TCC on GM12878 (Tier 1) with MboI - 4DNEX9BBS4IQ", "external_references": [], "experiment_sets": [{"accession": "4DNESHTTKZYB", "experimentset_type": "replicate", "@type": ["ExperimentSetReplicate", "ExperimentSet", "Item"], "uuid": "2483aaaa-3053-4465-ac84-9485635fb92a", "@id": "/experiment-set-replicates/4DNESHTTKZYB/", "display_title": "4DNESHTTKZYB", "status": "released", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}], "produced_in_pub": {"title": "Cryomilling Tethered Chromatin Conformation Capture reveal new insights into inter-chromosomal interactions", "display_title": "Xu J et al. (2022) doi:10.1101/2022.02.03.478915", "status": "current", "@type": ["Publication", "Item"], "abstract": "Traditional methods used to map the three-dimensional organization of chromatin in-situ generally involve chromatin conformation capture by formaldehyde crosslinking, followed by detergent solubilization and enzymatic digestion of DNA. Ligation of proximal DNA fragments followed by next generation sequencing (NGS) generates contact information that enables a global view of the chromatin conformation. Here, we explore the use of cryomilling to physically fragmentize the cells under cryogenic conditions to probe chromatin interactions in the cryomilled cell fragments by the tethered chromatin conformation capture (TCC). Our results show that cryomilling TCC (CTCC) can generate a global contact map similar to that obtained with in-situ Hi-C. This result suggests that summation of chromatin interactions mapped in individual subcellular fragments can reconstitute the global contact map of intact cells in an ensemble manner, paving the way for chromatin conformation analyses of solid tissue by CTCC. Compared with the conventional in-situ methods such as Hi-C, CTCC shows more uniform access to different subcompartments of the folded genome. On the other hand, most inter-chromosomal (trans) contacts are diminished or lost in CTCC except for a group of unique trans contacts that remain intact throughout the cryomilling and in- vitro crosslinking steps. These apparently ultra-stable trans interactions have much enhanced signal in CTCC due to the elimination of signals of most, presumably weak and transient trans interactions. Systematic and comparative analyses between CTCC and in-situ Hi-C provide further insights into the chromatin structure organization and reveal a generally unentangled chromosome interface and the existence of stable inter-chromosomal contacts that may represent intermingled inter-chromosomal interfaces.", "@id": "/publications/1eff3a17-6ed5-46be-9767-a11761974c12/", "authors": ["Xu J", "Kumar S", "Hua N", "Kou Y", "Lei X", "Rout M", "Aitchison J", "Alber F", "Chen L"], "ID": "doi:10.1101/2022.02.03.478915", "uuid": "1eff3a17-6ed5-46be-9767-a11761974c12", "journal": "bioRxiv", "date_published": "2022-02-12", "short_attribution": "Xu J et al. (2022)", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, "publications_of_exp": [{"date_published": "2022-02-12", "abstract": "Traditional methods used to map the three-dimensional organization of chromatin in-situ generally involve chromatin conformation capture by formaldehyde crosslinking, followed by detergent solubilization and enzymatic digestion of DNA. Ligation of proximal DNA fragments followed by next generation sequencing (NGS) generates contact information that enables a global view of the chromatin conformation. Here, we explore the use of cryomilling to physically fragmentize the cells under cryogenic conditions to probe chromatin interactions in the cryomilled cell fragments by the tethered chromatin conformation capture (TCC). Our results show that cryomilling TCC (CTCC) can generate a global contact map similar to that obtained with in-situ Hi-C. This result suggests that summation of chromatin interactions mapped in individual subcellular fragments can reconstitute the global contact map of intact cells in an ensemble manner, paving the way for chromatin conformation analyses of solid tissue by CTCC. Compared with the conventional in-situ methods such as Hi-C, CTCC shows more uniform access to different subcompartments of the folded genome. On the other hand, most inter-chromosomal (trans) contacts are diminished or lost in CTCC except for a group of unique trans contacts that remain intact throughout the cryomilling and in- vitro crosslinking steps. These apparently ultra-stable trans interactions have much enhanced signal in CTCC due to the elimination of signals of most, presumably weak and transient trans interactions. Systematic and comparative analyses between CTCC and in-situ Hi-C provide further insights into the chromatin structure organization and reveal a generally unentangled chromosome interface and the existence of stable inter-chromosomal contacts that may represent intermingled inter-chromosomal interfaces.", "journal": "bioRxiv", "status": "current", "short_attribution": "Xu J et al. (2022)", "display_title": "Xu J et al. (2022) doi:10.1101/2022.02.03.478915", "title": "Cryomilling Tethered Chromatin Conformation Capture reveal new insights into inter-chromosomal interactions", "uuid": "1eff3a17-6ed5-46be-9767-a11761974c12", "ID": "doi:10.1101/2022.02.03.478915", "@type": ["Publication", "Item"], "authors": ["Xu J", "Kumar S", "Hua N", "Kou Y", "Lei X", "Rout M", "Aitchison J", "Alber F", "Chen L"], "@id": "/publications/1eff3a17-6ed5-46be-9767-a11761974c12/", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}], "experiment_categorizer": {"field": "Enzyme", "value": "MboI", "combined": "Enzyme: MboI"}, "experiment_summary": "TCC on GM12878 (Tier 1) with MboI", "@context": "/terms/", "aggregated-items": {"badges": [{"parent": "/biosamples/4DNBS1JXRD84/", "embedded_path": "biosample.badges", "item": {"messages": ["Biosample missing morphology_image"], "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": []}