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A detailed understanding of the spatial arrangement of the human genome, referred to as the 4D nucleome, and the biological and physical principles that drive chromosome folding requires combining approaches from the fields of molecular and cell biology, imaging, genetics and genomics with approaches from physics, computational biology, and computer simulation. We have assembled a highly interdisciplinary center with the goal of generating extensively validated maps of the 4D nucleome, its physical and dynamic properties and its role in regulating the activity of the genome. First, the center will further optimize and extensively validate a suite of genome-wide molecular methodologies, based on chromosome conformation capture (3C) that can probe the folding of chromosomes at the scale of single nucleosomes, chromatin fibers, chromosomes and the entire nucleus, across cell populations and in single cells. Given that chromosome and nuclear organization is tightly linked to biological state of the cell, the center will map the 4D nucleome for four key biological states representing different conformations during the cell cycle (interphase and mitosis), and during cell differentiation (pluripotent and differentiated states). We will obtain complementary data regarding the structure and dynamics of chromatin, at different length scales and in single cells using extensive high-throughput imaging, live cell imaging and super resolution microscopy. Data obtained with all approaches will be analyzed, integrated and modeled using a set of methods we will further develop to gain insights into the structure, physics and dynamics of chromosome folding over different length scales. Finally, a critical component of our proposal is the biological validation and further elaboration of the chromatin interaction maps that are generated from our conformational analyses. 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organization have recently been  established, including non-random positioning of chromosomes and genes in the  cell nucleus, distinct chromatin compartments, and topologically associating  domains (TADs). However, the extent and nature of cell-to-cell and cell-intrinsic  variability in genome architecture are still poorly characterized. Here, we  systematically probe heterogeneity in genome organization. High-throughput  optical mapping of several hundred intra-chromosomal interactions in individual  human fibroblasts demonstrates low association frequencies, which are determined  by genomic distance, higher-order chromatin architecture, and chromatin  environment. The structure of TADs is variable between individual cells, and  inter-TAD associations are common. Furthermore, single-cell analysis reveals  independent behavior of individual alleles in single nuclei. Our observations  reveal extensive variability and heterogeneity in genome organization at the  level of individual alleles and demonstrate the coexistence of a broad spectrum  of genome configurations in a cell population.", "url": "https://www.ncbi.nlm.nih.gov/pubmed/30799036", "uuid": "80007b23-7748-4492-9e49-c38400acbe60", "short_attribution": "Finn EH et al. (2019)", "@id": "/publications/80007b23-7748-4492-9e49-c38400acbe60/", "status": "current", "display_title": "Finn EH et al. (2019) PMID:30799036", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, "pubs_using": [], "publications_of_set": [{"@id": "/publications/80007b23-7748-4492-9e49-c38400acbe60/", "ID": "PMID:30799036", "status": "current", "journal": "Cell", "uuid": "80007b23-7748-4492-9e49-c38400acbe60", "date_published": "2019-03-07", "title": "Extensive Heterogeneity and Intrinsic Variation in Spatial Genome Organization.", "@type": ["Publication", "Item"], "display_title": "Finn EH et al. 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