Contactomics: Exploring New Dimensions of 3D Genome Architecture

Abstract

3D genome folding is increasingly recognized as an instrumental regulator of gene expression. This thesis contains two literature reviews in which the current knowledge regarding genome folding and function is described; chapter one focusses on the implications for gene regulation at each hierarchical level of genome folding and addresses the factors that are believed to fold the genome at each level. In chapter two, the unique 3D folding of the pluripotent genome is discussed. The three experimental chapters of this thesis describe the results of three studies, aimed to gain a better understanding of the relationship between genome form and function. Chapter three describes specific features of the 3D genome of pluripotent stem cells, and how these are lost and gained during differentiation and reprogramming. Chapter four focusses on the development of a novel method to study genome conformation: multi-contact chromosome conformation capture sequencing, which allows studying of multi-way chromatin conformation and chromatin hubs. The final chapter describes a collaborative study in which the chromatin dynamics of enhancer-promoter contacts are followed during in vitro cardiomyocyte differentiation. Together, the chapters of this thesis illustrate the importance of studying gene expression in the context of the 3D nucleus.