Patterns and processes driving chromosome organization

Abstract

In this thesis, we focus on different approaches to studying the organization of chro­mosomes with in the nucleus of cells. We employ both genomic analysis of chromo­some interaction maps, and polymer simulations to answer various questions that are relevant to the field.

The first two chapters of this thesis are centered around genomic analysis of inter­action maps generated from Chromosome Conformation Capture (3C) technologies. We begin by analyzing data generated using a novel Micro-C protocol and assess its performance in comparison to established Hi-C. New computation tools are developed to extract, quantify and compare patterns detected in both techniques. We find that Micro-C can accurately recapitulate the patterns of interactions found in Hi-C. In addition, evidence for nucleosome scale structure is also detected in the data.

Following this, the scope of the meta-analysis is expanded. We compared over 70 different human Hi-C and Micro-C libraries that vary in the biochemical parameters used in data generation. We extract trends that relate the protocol parameters to the observed patterns of enrichment found in the data. We find that libraries generated with a high degree of fragmentation are better at capturing fine scale organization, while those with larger fragments excel in capturing larger patterns and structures.

In the final chapter, we explore the dynamic changes in chromosome organization through the early stages of cell division. We analyze experimental Hi-C of DT-40 chicken cells and uncover the role of Condensin in disassembling interphase chromatin structure during prophase. We develop a model for prophase condensation and explore different interactions between loop extruding Cohesins and Condensins. We find that non-trivial interactions between these complexes are required to accurately capture the dynamics of the data. Our findings extend the model of loop extrusion and highlight the role of interactions between SMC complexes in organizing chromosomes.