Unfolding genome organization in interphase
Name
1121596255-MIT.pdf
Size
17.77 MB
Format
Adobe PDF
Checksum (MD5)
611d6f3195e1d10dea7bcdb53a331a75
Author(s)
Abdennur, Nezar Alexander
Advisor(s)
Leonid Mirny.
Date Issued
2019
Publisher
Massachusetts Institute of Technology
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.
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).
Subjects
Computational and Systems Biology Program.
MIT Department
Massachusetts Institute of Technology. Computational and Systems Biology Program
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