Chapter 6 Discussion

Recent developments in proximity-ligation methods allow measuring of pairwise chromatin interactions genome-wide. Resulting interaction maps revealed a hierarchical organization of genome folding with the property of interphase chromosomes to fold into frequently interacting domains, called TADs. This non-random organization lead to many fundamental questions of how genome folding contributes to functional segregation in genomes and how domain organization ensures precise regulation of gene expression (Chapter 1).

Chromatin interaction data can be integrated computationally with one-dimensional measurements along the genome. This allows annotating folding structures with diverse functional data such as epigenetic marks, protein binding signals, tissue-specific gene expression, or sequence conservation across genomes. Work in this thesis applied such approaches to analyze the function of TADs for gene regulation in the contexts of evolution and diseases. The results highlight the role of TADs as regulatory environments for gene expression, their stability during millions of years of evolution as well as their disruptions by disease-associated genetic variants. Furthermore, recent insights into molecular mechanisms of chromatin loop formation are used to predict long-range interactions genome-wide from protein binding data.

This section discusses the results of chapters 2, 3, 4, and 5 in light of the most recent literature and suggests further research perspectives.