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Title: The role of cohesin in long-range gene regulation
Author: Ing-Simmons, Elizabeth
ISNI:       0000 0004 6348 476X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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The cohesin complex holds together sister chromatids after DNA replication: this is vital for correct segregation of chromosomes into daughter cells at mitosis. As well as this cell cycle role, cohesin has been implicated in regulating gene expression during interphase, through cohesin-mediated interactions between genes and regulatory elements. Such regulatory interactions tend to take place within topological domains. Topological domains are genomic regions which have preferential self-interactions in the 3D organisation of chromatin within the nucleus. Domain boundaries are enriched for cohesin and its frequent binding partner CTCF, and depletion of cohesin has been shown to affect genome organisation into topological domains, as well as causing the loss of enhancer–promoter interactions at some loci. However, it is unclear how cohesin-mediated interactions influence gene expression genome-wide. In this thesis, I use comparisons of control and cohesin-deficient mouse thymocytes to show that cohesin-mediated interactions between enhancers are important for the regulation of gene expression. Cohesin and CTCF are enriched at enhancers, and particularly at clusters of enhancer elements known as "super-enhancers". Cohesin mediates interactions between these enhancer elements, leading to their spatial clustering. While H3K27ac, H3K4me1, and transcription at enhancers are not affected by cohesin depletion, interactions between enhancer elements are lost. Enhancer-proximal genes are preferentially deregulated in cohesin-deficient cells, suggesting that these interactions are important for gene regulation. Deregulation of gene expression tends to occur in a coordinated manner within topological domains, which emphasises the importance of the structural organisation of the genome for gene regulation. Therefore, in this thesis I also consider models for the processes shaping genome organisation. I present evidence supporting key roles for cohesin and CTCF in these processes. Taken together, these results show that cohesin is important for both the organisation of topological domains and regulatory interactions within them.
Supervisor: Merkenschlager, Matthias ; Lenhard, Boris Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral