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). / 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. / by Nezar Abdennur. / Ph. D. / Ph.D. Massachusetts Institute of Technology, Computational and Systems Biology Program
| Identifer | oai:union.ndltd.org:MIT/oai:dspace.mit.edu:1721.1/122537 |
| Date | January 2019 |
| Creators | Abdennur, Nezar(Nezar Alexander) |
| Contributors | Leonid Mirny., Massachusetts Institute of Technology. Computational and Systems Biology Program., Massachusetts Institute of Technology. Computational and Systems Biology Program |
| Publisher | Massachusetts Institute of Technology |
| Source Sets | M.I.T. Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 166 pages, application/pdf |
| 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., http://dspace.mit.edu/handle/1721.1/7582 |
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