{"lab": {"@id": "/labs/erez-liebermanaiden-lab/", "@type": ["Lab", "Item"], "display_title": "Erez Lieberman Aiden, BCM", "title": "Erez Lieberman Aiden, BCM", "uuid": "5771d772-1d10-43ea-bec1-0ea8c5a58503", "correspondence": [{"contact_email": "ZXJlekBlcmV6LmNvbQ==", "@id": "/users/60938b2e-e120-4c4f-9ddb-001296021df7/", "display_title": "Erez Lieberman Aiden"}], "status": "current", "pi": {"error": "no view permissions"}, "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin", "role.lab_submitter", "submits_for.5771d772-1d10-43ea-bec1-0ea8c5a58503"]}}, "award": {"name": "OD008540-01", "@type": ["Award", "Item"], "@id": "/awards/OD008540-01/", "uuid": "36a06537-7831-494d-b10d-3e9fea931021", "status": "current", "display_title": "EXPLORING HOW THE GENOME FOLDS THROUGH PROXIMITY LIGATION AND SEQUENCING", "project": "External", "center_title": "Lieberman Aiden", "description": "Biological systems contain a large number of components whose physical interactions bring about cellular processes. A fundamental problem in molecular biology is to catalog these interactions and to decipher their functional consequences. High throughput sequencing has made it possible to characterize some of these interactions rapidly, at high-resolution, and in vivo (e.g., protein-DNA binding via ChIP-Seq and protein-RNA binding via RIP-Seq). But many interactions are not susceptible to these methods (e.g., RNA- RNA complexes, ncRNA-DNA binding, and - aside from recent work described below - DNA-DNA contacts and genome folding.) This gap may be bridged by coupling high-throughput sequencing with proximity-ligation-based methods. In proximity ligation, spatially proximate nucleic acids ligate to one another, forming a chimeric oligo. Observation of a chimera composed of X and Y suggests that X and Y must have been near one another in the original sample. As a result, questions about spatial arrangement become questions about sequence composition, making it possible to take advantage of high-throughput sequencing. Nevertheless, the development of these approaches is challenging: they involve subtle molecular biology and produce massive high-dimensional datasets requiring wholly new analytical paradigms including extensive physical modeling. We recently developed Hi-C, the first technology that couples proximity ligation and high-throughput sequencing in an unbiased, genome-wide fashion (Lieberman-Aiden et al., Science, 2009). Hi-C uses a DNA-DNA proximity ligation step to identify long-range physical contacts between genomic DNA loci in vivo. We used Hi-C to create a low-resolution three-dimensional map of the human genome, and made two significant discoveries: (1) genetic regulation is accompanied by the three-dimensional movement of genes from an 'on' compartment to an 'off' compartment, and vice-versa; (2) a never-before-seen macromolecular state, the fractal globule, which couples extraordinary spatial density and a total absence of knots. Here, we propose to dramatically extend the above work, by building a new generation of tools for systematically exploring the spatial organization of genomes, RNAs, and proteins, and by applying these tools to explore how RNAs and proteins establish and regulate the three-dimensional architecture of the genome. We will accomplish this through three specific research aims: (1) We will create an ensemble of new technologies combining proximity ligation and sequencing to enable comprehensive mapping of (a) DNA-RNA contacts [via DNA-RNA proximity ligation]; (b) RNA-RNA complexes [via RNA-RNA proximity ligation]; (c) selected protein-protein complexes [via probe-coupled proximity ligation]. We will use these methods to generate maps of biomolecular contacts in vivo. (2) We will create high-resolution Hi-C maps of mammalian genomes, comprehensively mapping promoter-enhancer contacts and exploring large-scale organizational features such as transcription factories. (3) We will develop new analytical approaches that combine the data produced by (1) and (2) with new (a) informatic tools, (b) computational analyses, (c) physical simulations, and (d) rigorous theoretical methods. We will characterize how physical interactions change during differentiation and tumorigenesis; identify the RNAs, proteins and pathways that that are most crucial in regulating genome folding, and produce detailed physical models of these pathways and how they modulate the physical structure of the genome. We plan to initially apply these techniques to characterize murine ES cells differentiating down a neural lineage, and later to differentiating human ES cells and to primary tumors. This effort will produce powerful new molecular methods which will dramatically improve our ability to assess the spatial arrangement of cellular components. It will transform our understanding of how mammalian genomes fold inside the nucleus. It will reveal how specific physical interactions between DNA, RNA, and protein play a role in differentiation, tumorigenesis, and genome folding, and suggest new drug targets in the process. Finally, this work will generate a series of datasets that will serve as valuable resources for the scientific community as a whole. Public Health Relevance: Biological systems contain a large number of components whose physical interactions bring about cellular processes, but our tools for identifying many of these biomolecular interactions are laborious and slow. We recently developed the Hi-C method for reconstructing the architecture of the human genome, and will extend this technological approach to map interactions between DNA, RNA, and protein in vivo and at high-throughput. 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"4DNESEOQUGG3", "experimentset_type": "custom", "display_title": "4DNESEOQUGG3", "@type": ["ExperimentSet", "Item"], "@id": "/experiment-sets/4DNESEOQUGG3/", "uuid": "b5e7dbe9-6ebe-468e-8d02-45ff6ca04ce8", "status": "released", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, {"accession": "4DNES3JX38V5", "experimentset_type": "replicate", "display_title": "4DNES3JX38V5", "@type": ["ExperimentSetReplicate", "ExperimentSet", "Item"], "@id": "/experiment-set-replicates/4DNES3JX38V5/", "uuid": "aa6f0d82-16c9-4109-a1f8-3fa0636a3560", "status": "released", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}], "produced_in_pub": {"authors": ["Rao SS", "Huntley MH", "Durand NC", "Stamenova EK", "Bochkov ID", "Robinson JT", "Sanborn AL", "Machol I", "Omer AD", "Lander ES", "Aiden EL"], "@id": "/publications/cf0e49aa-173c-49d1-a7c7-22acbc83c064/", "title": "A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping.", "ID": "PMID:25497547", "short_attribution": "Rao SS et al. (2014)", "uuid": "cf0e49aa-173c-49d1-a7c7-22acbc83c064", "abstract": "We use in situ Hi-C to probe the 3D architecture of genomes, constructing haploid and diploid maps of nine cell types. The densest, in human lymphoblastoid cells,  contains 4.9 billion contacts, achieving 1 kb resolution. We find that genomes are partitioned into contact domains (median length, 185 kb), which are associated with distinct patterns of histone marks and segregate into six subcompartments. We identify approximately 10,000 loops. These loops frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species. Loop anchors typically occur at domain boundaries and bind CTCF. CTCF sites at loop anchors occur predominantly (>90%) in a convergent orientation, with the asymmetric motifs \"facing\" one another. The inactive X chromosome splits into two massive domains and contains large loops anchored at CTCF-binding repeats.", "display_title": "Rao SS et al. (2014) PMID:25497547", "journal": "Cell", "date_published": "2014-12-11", "@type": ["Publication", "Item"], "status": "current", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, "publications_of_exp": [{"date_published": "2023-11-06", "uuid": "d23f7a68-6b66-493c-9011-d1bde9fcfd04", "authors": ["Erdmann-Pham DD", "Batra SS", "Turkalo TK", "Durbin J", "Blanchette M", "Yeh I", "Shain H", "Bastian BC", "Song YS", "Rokhsar DS", "Hockemeyer D"], "title": "Tracing cancer evolution and heterogeneity using Hi-C.", "@id": "/publications/d23f7a68-6b66-493c-9011-d1bde9fcfd04/", "abstract": "Chromosomal rearrangements can initiate and drive cancer progression, yet it has  been challenging to evaluate their impact, especially in genetically  heterogeneous solid cancers. To address this problem we developed HiDENSEC, a new  computational framework for analyzing chromatin conformation capture in  heterogeneous samples that can infer somatic copy number alterations,  characterize large-scale chromosomal rearrangements, and estimate cancer cell  fractions. After validating HiDENSEC with in silico and in vitro controls, we  used it to characterize chromosome-scale evolution during melanoma progression in  formalin-fixed tumor samples from three patients. The resulting comprehensive  annotation of the genomic events includes copy number neutral translocations that  disrupt tumor suppressor genes such as NF1, whole chromosome arm exchanges that  result in loss of CDKN2A, and whole-arm copy-number neutral loss of homozygosity  involving PTEN. These findings show that large-scale chromosomal rearrangements  occur throughout cancer evolution and that characterizing these events yields  insights into drivers of melanoma progression.", "@type": ["Publication", "Item"], "ID": "PMID:37932252", "display_title": "Erdmann-Pham DD et al. (2023) PMID:37932252", "short_attribution": "Erdmann-Pham DD et al. (2023)", "status": "current", "journal": "Nature communications", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, {"date_published": "2023-02-22", "uuid": "10a8b77d-571e-4442-baf4-47a8bd0fca84", "authors": ["Kariti H", "Feld T", "Kaplan N"], "title": "Hypothesis-driven probabilistic modelling enables a principled perspective of  genomic compartments.", "@id": "/publications/10a8b77d-571e-4442-baf4-47a8bd0fca84/", "abstract": "The Hi-C method has revolutionized the study of genome organization, yet  interpretation of Hi-C interaction frequency maps remains a major challenge.  Genomic compartments are a checkered Hi-C interaction pattern suggested to  represent the partitioning of the genome into two self-interacting states  associated with active and inactive chromatin. Based on a few elementary  mechanistic assumptions, we derive a generative probabilistic model of genomic  compartments, called deGeco. Testing our model, we find it can explain observed  Hi-C interaction maps in a highly robust manner, allowing accurate inference of  interaction probability maps from extremely sparse data without any training of  parameters. Taking advantage of the interpretability of the model parameters, we  then test hypotheses regarding the nature of genomic compartments. We find clear  evidence of multiple states, and that these states self-interact with different  affinities. We also find that the interaction rules of chromatin states differ  considerably within and between chromosomes. Inspecting the molecular  underpinnings of a four-state model, we show that a simple classifier can use  histone marks to predict the underlying states with 87% accuracy. Finally, we  observe instances of mixed-state loci and analyze these loci in single-cell Hi-C  maps, finding that mixing of states occurs mainly at the cell level.", "@type": ["Publication", "Item"], "ID": "PMID:36629266", "display_title": "Kariti H et al. (2023) PMID:36629266", "short_attribution": "Kariti H et al. (2023)", "status": "current", "journal": "Nucleic acids research", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, {"date_published": "2014-12-11", "uuid": "cf0e49aa-173c-49d1-a7c7-22acbc83c064", "authors": ["Rao SS", "Huntley MH", "Durand NC", "Stamenova EK", "Bochkov ID", "Robinson JT", "Sanborn AL", "Machol I", "Omer AD", "Lander ES", "Aiden EL"], "title": "A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping.", "@id": "/publications/cf0e49aa-173c-49d1-a7c7-22acbc83c064/", "abstract": "We use in situ Hi-C to probe the 3D architecture of genomes, constructing haploid and diploid maps of nine cell types. The densest, in human lymphoblastoid cells,  contains 4.9 billion contacts, achieving 1 kb resolution. We find that genomes are partitioned into contact domains (median length, 185 kb), which are associated with distinct patterns of histone marks and segregate into six subcompartments. We identify approximately 10,000 loops. These loops frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species. Loop anchors typically occur at domain boundaries and bind CTCF. CTCF sites at loop anchors occur predominantly (>90%) in a convergent orientation, with the asymmetric motifs \"facing\" one another. The inactive X chromosome splits into two massive domains and contains large loops anchored at CTCF-binding repeats.", "@type": ["Publication", "Item"], "ID": "PMID:25497547", "display_title": "Rao SS et al. (2014) PMID:25497547", "short_attribution": "Rao SS et al. (2014)", "status": "current", "journal": "Cell", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, {"date_published": "2022-10", "uuid": "b78174a0-b747-4826-bdd6-276e6697c5f2", "authors": ["Deshpande AS", "Ulahannan N", "Pendleton M", "Dai X", "Ly L", "Behr JM", "Schwenk S", "Liao W", "Augello MA", "Tyer C", "Rughani P", "Kudman S", "Tian H", "Otis HG", "Adney E", "Wilkes D", "Mosquera JM", "Barbieri CE", "Melnick A", "Stoddart D", "Turner DJ", "Juul S", "Harrington E", "Imielinski M"], "title": "Identifying synergistic high-order 3D chromatin conformations from genome-scale  nanopore concatemer sequencing.", "@id": "/publications/b78174a0-b747-4826-bdd6-276e6697c5f2/", "abstract": "High-order three-dimensional (3D) interactions between more than two genomic loci  are common in human chromatin, but their role in gene regulation is unclear.  Previous high-order 3D chromatin assays either measure distant interactions  across the genome or proximal interactions at selected targets. To address this  gap, we developed Pore-C, which combines chromatin conformation capture with  nanopore sequencing of concatemers to profile proximal high-order chromatin  contacts at the genome scale. We also developed the statistical method Chromunity  to identify sets of genomic loci with frequencies of high-order contacts  significantly higher than background ('synergies'). Applying these methods to  human cell lines, we found that synergies were enriched in enhancers and  promoters in active chromatin and in highly transcribed and lineage-defining  genes. In prostate cancer cells, these included binding sites of androgen-driven  transcription factors and the promoters of androgen-regulated genes. Concatemers  of high-order contacts in highly expressed genes were demethylated relative to  pairwise contacts at the same loci. Synergies in breast cancer cells were  associated with tyfonas, a class of complex DNA amplicons. These results  rigorously link genome-wide high-order 3D interactions to lineage-defining  transcriptional programs and establish Pore-C and Chromunity as scalable  approaches to assess high-order genome structure.", "@type": ["Publication", "Item"], "ID": "PMID:35637420", "display_title": "Deshpande AS et al. (2022) PMID:35637420", "short_attribution": "Deshpande AS et al. (2022)", "status": "current", "journal": "Nature biotechnology", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}], "experiment_categorizer": {"field": "Enzyme", "value": "MboI", "combined": "Enzyme: MboI"}, "experiment_summary": "in situ Hi-C on GM12878 with MboI", "@context": "/terms/", "aggregated-items": {"badges": [{"parent": "/biosamples/4DNBSBUH7SNR/", "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": []}