Organisation and evolution of landscapes of gene regulation
File(s)
Author(s)
King, James
Type
Thesis
Abstract
The control of developmentally expressed genes is highly complex, requiring input from multiple layers of regulation. Among the least understood of those layers are long-range enhancer-promoter interactions and the organisation of the architecture of chromatin folding. Alterations in these aspects of regulation are likely to underlie the establishment of differences across a range of contexts, from determining cell fate to defining species-specific traits. The CTCF protein and the cohesin complex play key roles in defining 3D chromatin architecture, and are thought to be critical in directing patterns of gene expression. Yet, previous cohesin and CTCF depletion studies cast doubt on their importance in this context. In this thesis I show, using thymocyte differentiation as a model, how developmentally regulated genes are particularly sensitive to cohesin and CTCF, providing evidence regarding the importance of cohesin, CTCF and general 3D structure in the coordination of complex regulation. I uncover surprising dissimilarity in the identities of genes affected by each depletion, and demonstrate how this is caused by differences in how each depletion affects 3D structure, further highlighting how 3D space influences gene expression. I then focus on how changes in long-range regulation occur over evolutionary timescales. I Identify signatures of acceleration in otherwise conserved elements across mammals, presenting evidence that a subset of generally conserved elements are predisposed to shifts in selection pressure. Across studied species these regions are particularly enriched for activity in the developing brain. Furthermore, I show how GC-biased gene conversion is a regular source of lineage-specific gain in CpG Islands in conserved elements for a subset of species. This is further evidence that the repurposing of existing elements is a viable route through which evolutionary innovation occurs. Taken together, this work reveals detailed aspects of the organisation of long-range regulation, both in nuclear space and over evolutionary time.
Version
Open Access
Date Issued
2022-07
Date Awarded
2023-11
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Lenhard, Boris
Publisher Department
Institute of Clinical Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)