Exploring mammalian chromatin architecture and its impact on gene regulation

Thesis

Mammalian chromatin architecture appears hierarchically organised and is composed of chromosome territories, compartments, topologically associating domains (TADs), loops and nucleosomes. The study of chromatin architecture has recently become prevalent due to the advancement of chromosome conformation capture (3C) and microscopy-based techniques. Many studies have predicted that TADs display important functional characteristics such as forming tissue and species-invariant regulatory domains, promoting co-regulation and insulating genes from aberrant regulation. Even with the increasing availability of data, the relationship between chromatin structures such as TADs, gene expression and function is still not fully understood. In this thesis, I use publicly available Hi-C data to rigorously assess this relationship.

To further investigate the characteristics of TADs I compiled a re-annotated TAD dataset consisting of 13 human and 20 mouse genomes, covering 8 broad tissue/cell type groups. Using this TAD dataset as a foundation, I investigated the functional features of TADs in three main areas: tissue and species specificity, functional annotations, and phenotypic characteristics. Comparative analyses between TADs and randomly placed TADs revealed that there is some evidence that TADs are both tissue- and species-specific, genes which singly occupy a TAD are highly constrained and enriched for developmental functions, and genes sharing a CTCF TAD are not more functionally similar than can be explained by their linear proximity alone. Lastly, using adipose TADs as well as chromatin loops, I investigate the aetiology of genetic variants associated with fat distribution.

The comprehensive analyses outlined suggest that contrary to common claims in the literature, TADs display a significant degree of both tissue and species specificity and play a limited role in promoting gene co-expression. These results contribute to understanding the relationship between 3D mammalian chromatin structure and gene regulation which is crucial for dissecting gene regulatory programs.

Authors: Long, HS

• DOI: 10.5287/ora-noxmwezbq
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: TADs; Hi-C
• Subjects: Topologically associating domains; Genetic regulation; Chromatin architecture