{"id":{"repo_id":"mit","oai_identifier":"oai:dspace.mit.edu:1721.1/122537"},"canonical_url":"https://search.dev.ndltd.org/etd/mit/oai:dspace.mit.edu:1721.1/122537","repository":{"repo_id":"mit","name":"MIT","base_url":"https://dspace.mit.edu/oai/request"},"display":{"title":"Unfolding genome organization in interphase","abstract":"Genomic contact frequency maps obtained from high throughput chromosome conformation capture technologies have revealed several organizing patterns of mammalian interphase chromosomes, including self-interacting topologically associating domains (TADs) which are believed to function as coherent gene regulatory neighborhoods. However, the mechanisms driving these patterns are still unknown. In this thesis, I describe and apply computational methods that test the predictions of a recently proposed loop extrusion model in the context of experimental perturbations of its key molecular players. In the first project I introduce a new data model, file format, and supporting software package to cope with the challenges of the increasing size and resolution of Hi-C datasets, including a parallel and scalable matrix balancing implementation.","abstract_html":"Genomic contact frequency maps obtained from high throughput chromosome conformation capture technologies have revealed several organizing patterns of mammalian interphase chromosomes, including self-interacting topologically associating domains (TADs) which are believed to function as coherent gene regulatory neighborhoods. However, the mechanisms driving these patterns are still unknown. In this thesis, I describe and apply computational methods that test the predictions of a recently proposed loop extrusion model in the context of experimental perturbations of its key molecular players. In the first project I introduce a new data model, file format, and supporting software package to cope with the challenges of the increasing size and resolution of Hi-C datasets, including a parallel and scalable matrix balancing implementation.","abstract_has_math":false,"creators":["Abdennur, Nezar Alexander"],"institution":"Massachusetts Institute of Technology","degree_name":"Doctoral","degree_level":null,"degree_discipline":null,"degree_department":"Massachusetts Institute of Technology. Computational and Systems Biology Program","school":null,"contributors":[],"advisors":["Leonid Mirny."],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019","date_published":"2019","updated_at":"2026-07-22T22:20:57Z","subjects":["Computational and Systems Biology Program."],"languages":["eng"],"rights":["MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission."],"rights_urls":["http://dspace.mit.edu/handle/1721.1/7582"],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/1721.1/122537","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Leonid Mirny."]},{"key":"dc:contributor.department","label":"Department","values":["Massachusetts Institute of Technology. Computational and Systems Biology Program","CSB"]},{"key":"dc:contributor.other","label":"Dc Contributor Other","values":["Massachusetts Institute of Technology. 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They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission."]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://dspace.mit.edu/handle/1721.1/7582"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/1721.1/122537"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Thesis: Ph. D., Massachusetts Institute of Technology, Computational and Systems Biology Program, 2019","Cataloged from PDF version of thesis.","Includes bibliographical references (pages 147-166)."]},{"key":"dc:description.abstract","label":"Abstract","values":["Genomic contact frequency maps obtained from high throughput chromosome conformation capture technologies have revealed several organizing patterns of mammalian interphase chromosomes, including self-interacting topologically associating domains (TADs) which are believed to function as coherent gene regulatory neighborhoods. However, the mechanisms driving these patterns are still unknown. In this thesis, I describe and apply computational methods that test the predictions of a recently proposed loop extrusion model in the context of experimental perturbations of its key molecular players. In the first project I introduce a new data model, file format, and supporting software package to cope with the challenges of the increasing size and resolution of Hi-C datasets, including a parallel and scalable matrix balancing implementation.","In the second project, I show that depletion of the Structural Maintenance of Chromosomes (SMC) complex, cohesin, in non-cycling mouse liver cells completely eliminates the appearance of TADs in Hi-C maps while preserving genome compartmentalization. In the third project, I demonstrate that depletion of a closely related SMC complex, condensin II, which plays a major role in mitotic chromosome condensation but is also found in the nucleus in interphase, has no impact on gene expression or the maintenance of genome organization in non-dividing cells. In the final project, I compile further evidence for loop extrusion in interphase by employing a combination of polymer simulations and meta-analysis of several Hi-C studies that performed targeted perturbations to modulate the presence of cohesin and the insulator protein, CTCF, on chromatin.","Together, these projects show that rather than being folded in a hierarchical fashion, mammalian genomes in interphase are organized by at least two distinct and antagonistic processes: global compartmental segregation dependent on epigenetic state, and local compaction dependent on cohesin. The latter process is likely to be the dynamic extrusion of chromatin loops driven by a yet-to-be-characterized motor activity of cohesin complexes and limited by DNA-bound CTCF extrusion barriers."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph. D."]},{"key":"dc:title","label":"Title","values":["Unfolding genome organization in interphase"]}]}],"canonical_facts":{"dc:contributor.advisor":["Leonid Mirny."],"dc:contributor.department":["Massachusetts Institute of Technology. Computational and Systems Biology Program","CSB"],"dc:contributor.other":["Massachusetts Institute of Technology. Computational and Systems Biology Program."],"dc:creator":["Abdennur, Nezar Alexander"],"dc:date.accessioned":["2019-10-11T22:10:52Z"],"dc:date.available":["2019-10-11T22:10:52Z"],"dc:date.issued":["2019"],"dc:description":["Thesis: Ph. D., Massachusetts Institute of Technology, Computational and Systems Biology Program, 2019","Cataloged from PDF version of thesis.","Includes bibliographical references (pages 147-166)."],"dc:description.abstract":["Genomic contact frequency maps obtained from high throughput chromosome conformation capture technologies have revealed several organizing patterns of mammalian interphase chromosomes, including self-interacting topologically associating domains (TADs) which are believed to function as coherent gene regulatory neighborhoods. However, the mechanisms driving these patterns are still unknown. In this thesis, I describe and apply computational methods that test the predictions of a recently proposed loop extrusion model in the context of experimental perturbations of its key molecular players. In the first project I introduce a new data model, file format, and supporting software package to cope with the challenges of the increasing size and resolution of Hi-C datasets, including a parallel and scalable matrix balancing implementation.","In the second project, I show that depletion of the Structural Maintenance of Chromosomes (SMC) complex, cohesin, in non-cycling mouse liver cells completely eliminates the appearance of TADs in Hi-C maps while preserving genome compartmentalization. In the third project, I demonstrate that depletion of a closely related SMC complex, condensin II, which plays a major role in mitotic chromosome condensation but is also found in the nucleus in interphase, has no impact on gene expression or the maintenance of genome organization in non-dividing cells. In the final project, I compile further evidence for loop extrusion in interphase by employing a combination of polymer simulations and meta-analysis of several Hi-C studies that performed targeted perturbations to modulate the presence of cohesin and the insulator protein, CTCF, on chromatin.","Together, these projects show that rather than being folded in a hierarchical fashion, mammalian genomes in interphase are organized by at least two distinct and antagonistic processes: global compartmental segregation dependent on epigenetic state, and local compaction dependent on cohesin. The latter process is likely to be the dynamic extrusion of chromatin loops driven by a yet-to-be-characterized motor activity of cohesin complexes and limited by DNA-bound CTCF extrusion barriers."],"dc:description.degree":["Ph. D."],"dc:identifier.uri":["https://hdl.handle.net/1721.1/122537"],"dc:language.iso":["eng"],"dc:publisher":["Massachusetts Institute of Technology"],"dc:rights":["MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission."],"dc:rights.uri":["http://dspace.mit.edu/handle/1721.1/7582"],"dc:subject":["Computational and Systems Biology Program."],"dc:title":["Unfolding genome organization in interphase"],"dc:type":["Thesis"],"thesis:degree_name":["Doctoral"]},"updated_at":"2026-07-22T22:20:57Z"}