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Title: Regulatory landscapes associated with changes in nuclear architecture
Author: Olan, Ioana
ISNI:       0000 0004 7962 0308
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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Gene regulation is essential for establishing a cell's identity and relation with surrounding cells. A major role in modulating gene regulation is played by the cell's chromatin architecture. Gene positioning relative to the center of the nucleus or its three-dimensional contacts with other genomic regions can determine whether the gene is expressed or not. Changes in chromatin architecture have been reported in cell differentiation contexts, where the gene expression landscape undergoes striking remodelling. Architectural changes leading to abnormal expression levels have also been reported and linked to diseases, such as dementia or cancer. Chromatin is organised hierarchically, with interactions between regulatory regions such as enhancers and promoters being hosted within megabase-scale domains. Enhancer-promoter alterations have been mostly described in differentiation scenarios, while a number of studies concluded that such interactions are pre-looped within the same lineage. In this study, I characterised chromatin architecture coupled with gene expression changes in RAS-induced senescent (RIS) cells. RIS is a tumour suppressive phenotype associated with cell cycle arrest and inflammation, associated with substantial alterations in both chromatin architecture and expression profile. By combining data from Hi-C, ChIP-Seq and RNA-Seq experiments, I showed that enhancer-promoter interactions were altered during RIS. In particular, pro-inflammatory genes in the IL1 locus showed increased interactions with enhancers. I showed that chromatin alterations also occurred at larger scale, re-arranging the chromatin hierarchy. I used graph theoretical approaches to model the hierarchical organisation of the genome. I linked large scale re-arrangements in RIS to the formation of Senescence Associated Heterochromatic Foci (SAHF), an important phenotypic feature of RIS, consisting of striking re-organisation of heterochromatic regions. In terms of network connectivity, RIS interactions were characterised by increased separation between any two genomic regions. The present study extends the current knowledge regarding the potential for alterations of enhancer-promoter interactions within the same lineage. It also introduces new tools for characterising the chromatin hierarchy and determining multiple layers of organisation and their association. Such tools have the potential of resolving chromosome relative positioning and contextualising the consequences of copy number alterations.
Supervisor: Narita, Masashi Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: senescence ; chromatin ; network ; gene regulation ; community detection