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Increasing evidence indicates that specific genomic regions each associate with these compartments. This genome compartmentalization has been linked to various functions, but these links are still poorly understood. Interestingly, Lamina Associated Domains (LADs) share specific heterochromatin marks, defining chromatin domains with distinct genetic and epigenetic properties. Genomic regions associating with other nuclear compartments may similarly define distinct classes of chromatin domains. One major bottleneck towards a deeper understanding of nuclear organization has been the inability to convert microscopy views of nuclear compartments into genome-wide maps that show which loci are associated with which compartment, and how the chromosomal fiber traverses between compartments. In addition, there is an urgent need for more efficient methods to dissect the mechanisms by which large genomic regions are targeted to specific nuclear compartments. Finally, there is an urgent need for high-throughput approaches that query the functional relevance of genome compartmentalization. For this Center grant, we propose to meet these needs through the following Aims: 1. Develop a strategy that connects microscopy views to genome-wide maps that, together with modeling, reveal the localization and dynamics of genomic regions relative to all major nuclear compartments. 2. Develop methods for efficient manipulation of the genome in order to elucidate mechanisms that target loci to specific compartments. 3. Develop methods to measure, model, and validate the functional relevance of nuclear compartments. The combined results of these approaches will reveal causal relationships now hidden among entangled genomic, epigenetic, and nuclear organization features. Deliverables of this proposal include a wide range of structural and functional maps of nuclear organization, reagents for visualizing endogenous chromosome loci, a powerful pipeline for synthesis of ~100kb DNA fragments, and cell lines facilitating repeated, high-fidelity insertio of these large fragments back into selected sites in the genome. These resources will provide a powerful complement to other 4D Nucleome Consortium efforts. A key strength of this Center proposal is the experience and complementary research capabilities of its five Investigators. 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(2022)", "title": "Cohesin-mediated loop anchors confine the locations of human replication origins.", "uuid": "ee8db237-9a92-4b72-8292-a66028a95b5b", "abstract": "DNA replication occurs through an intricately regulated series of molecular events and is fundamental for genome stability(1,2). At present, it is unknown how the locations of replication origins are determined in the human genome. Here we dissect the role of topologically associating domains (TADs)(3-6), subTADs(7)  and loops(8) in the positioning of replication initiation zones (IZs). We stratify TADs and subTADs by the presence of corner-dots indicative of loops and  the orientation of CTCF motifs. We find that high-efficiency, early replicating IZs localize to boundaries between adjacent corner-dot TADs anchored by high-density arrays of divergently and convergently oriented CTCF motifs. By contrast, low-efficiency IZs localize to weaker dotless boundaries. Following ablation of cohesin-mediated loop extrusion during G1, high-efficiency IZs become diffuse and delocalized at boundaries with complex CTCF motif orientations. Moreover, G1 knockdown of the cohesin unloading factor WAPL results in gained long-range loops and narrowed localization of IZs at the same boundaries. Finally, targeted deletion or insertion of specific boundaries causes local replication timing shifts consistent with IZ loss or gain, respectively. Our data support a model in which cohesin-mediated loop extrusion and stalling at a subset of genetically encoded TAD and subTAD boundaries is an essential determinant of the locations of replication origins in human S phase.", "display_title": "Emerson DJ et al. (2022) PMID:35676475", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, "publications_of_exp": [{"ID": "PMID:35676475", "authors": ["Emerson DJ", "Zhao PA", "Cook AL", "Barnett RJ", "Klein KN", "Saulebekova D", "Ge C", "Zhou L", "Simandi Z", "Minsk MK", "Titus KR", "Wang W", "Gong W", "Zhang D", "Yang L", "Venev SV", "Gibcus JH", "Yang H", "Sasaki T", "Kanemaki MT", "Yue F", "Dekker J", "Chen CL", "Gilbert DM", "Phillips-Cremins JE"], "title": "Cohesin-mediated loop anchors confine the locations of human replication origins.", "uuid": "ee8db237-9a92-4b72-8292-a66028a95b5b", "abstract": "DNA replication occurs through an intricately regulated series of molecular events and is fundamental for genome stability(1,2). At present, it is unknown how the locations of replication origins are determined in the human genome. Here we dissect the role of topologically associating domains (TADs)(3-6), subTADs(7)  and loops(8) in the positioning of replication initiation zones (IZs). We stratify TADs and subTADs by the presence of corner-dots indicative of loops and  the orientation of CTCF motifs. We find that high-efficiency, early replicating IZs localize to boundaries between adjacent corner-dot TADs anchored by high-density arrays of divergently and convergently oriented CTCF motifs. By contrast, low-efficiency IZs localize to weaker dotless boundaries. Following ablation of cohesin-mediated loop extrusion during G1, high-efficiency IZs become diffuse and delocalized at boundaries with complex CTCF motif orientations. Moreover, G1 knockdown of the cohesin unloading factor WAPL results in gained long-range loops and narrowed localization of IZs at the same boundaries. Finally, targeted deletion or insertion of specific boundaries causes local replication timing shifts consistent with IZ loss or gain, respectively. Our data support a model in which cohesin-mediated loop extrusion and stalling at a subset of genetically encoded TAD and subTAD boundaries is an essential determinant of the locations of replication origins in human S phase.", "date_published": "2022-06-08", "journal": "Nature", "display_title": "Emerson DJ et al. (2022) PMID:35676475", "@type": ["Publication", "Item"], "status": "current", "short_attribution": "Emerson DJ et al. (2022)", "@id": "/publications/ee8db237-9a92-4b72-8292-a66028a95b5b/", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, {"ID": "PMID:38712201", "authors": ["Gholamalamdari O", "van Schaik T", "Wang Y", "Kumar P", "Zhang L", "Zhang Y", "Gonzalez GAH", "Vouzas AE", "Zhao PA", "Gilbert DM", "Ma J", "van Steensel B", "Belmont AS"], "title": "Beyond A and B Compartments: how major nuclear locales define nuclear genome  organization and function.", "uuid": "f2b3b3fb-e9af-484d-abeb-fe4316ffdc1a", "abstract": "Models of nuclear genome organization often propose a binary division into active  versus inactive compartments yet typically overlook nuclear bodies. Here we  integrated analysis of sequencing and image-based data to compare genome  organization in four human cell types relative to three different nuclear  locales: the nuclear lamina, nuclear speckles, and nucleoli. Whereas gene  expression correlates mostly with nuclear speckle proximity, DNA replication  timing correlates with proximity to multiple nuclear locales. Speckle attachment  regions emerge as DNA replication initiation zones whose replication timing and  gene composition vary with their attachment frequency. Most facultative LADs  retain a partially repressed state as iLADs, despite their positioning in the  nuclear interior. Knock out of two lamina proteins, Lamin A and LBR, causes a  shift of H3K9me3-enriched LADs from lamina to nucleolus, and a reciprocal  relocation of H3K27me3-enriched partially repressed iLADs from nucleolus to  lamina. Thus, these partially repressed iLADs appear to compete with LADs for  nuclear lamina attachment with consequences for replication timing. The nuclear  organization in adherent cells is polarized with nuclear bodies and genomic  regions segregating both radially and relative to the equatorial plane. Together,  our results underscore the importance of considering genome organization relative  to nuclear locales for a more complete understanding of the spatial and  functional organization of the human genome.", "date_published": "2025-02-26", "journal": "bioRxiv : the preprint server for biology", "display_title": "Gholamalamdari O et al. (2025) PMID:38712201", "@type": ["Publication", "Item"], "status": "current", "short_attribution": "Gholamalamdari O et al. (2025)", "@id": "/publications/f2b3b3fb-e9af-484d-abeb-fe4316ffdc1a/", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}], "experiment_categorizer": {"field": "Fraction", "value": "P6 of 17 fractions", "combined": "Fraction: P6 of 17 fractions"}, "experiment_summary": "Multi-stage Repli-seq on HCT116 (Tier 2) S-phase P6", "@context": "/terms/", "aggregated-items": {"badges": [{"parent": "/biosamples/4DNBST4UXQJ8/", "embedded_path": "biosample.badges", "item": {"messages": ["Biosample receives gold status for being a 4DN Tier 1 or Tier 2 cell line that follows the approved SOP and contains all of the pertinent metadata information as required by the 4DN Samples working group."], "badge": {"commendation": "Gold Biosample", "warning": null, "uuid": "6c2b7409-4478-4e15-aabc-1a0df6b883e9", "@id": "/badges/gold-biosample/", "badge_icon": "/static/img/badges/biosample-badge-gold-star.svg", "description": "Gold biosample"}}}]}, "validation-errors": []}