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Title: Genetic and epigenetic regulation of gene expression in pancreatic islets
Author: Nakic, Nikolina
ISNI:       0000 0004 7656 8778
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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T2D is a complex disease with evidence of a strong genetic basis. Studies of the human pancreatic islets have provided valuable insight into the islet regulatory landscape and identified enrichment of T2D-associated variants in islet enhancers. The relationship between cis-regulatory variation and changes in gene expression, however, remains unclear. This question is challenging to address in human, as it calls for a systematic analysis of cis-regulatory variation and the impact it has on gene expression in the native genomic context. While a mouse model can be used for this purpose, the regulatory landscape of the mouse pancreatic islets has been poorly characterized. This thesis addresses the questions of genetic and epigenetic regulation of gene expression in pancreatic islets in two parts. First, a genome-wide map of several histone modifications and transcription factor binding sites is created for the mouse pancreatic islet. This enabled identification of the mouse islet regulatory elements and characterization of enhancer clustering, transcription factor occupancy and conservation. A systematic comparison of enhancer clustering between mouse and human islets identified species-common and species-specific subsets of the islet regulatory program, each associated to a distinct biological function of the pancreatic islet. Second, a hybrid mouse was used as a model where naturally occurring genetic variation drives changes in gene expression. High-density mapping of allelic regulatory activity, chromatin accessibility and transcription provided insight into the properties of both genes subject to cis-regulatory variation and the regulatory elements driving the change in expression. As a result, tissue-specific genes associated to clustered enhancers were shown to be most influenced by cis-regulatory variation. Additionally, enhancer clustering emerged as the dominant property of regulatory elements associated to changes in gene expression. Overall, this thesis advanced our knowledge of the mouse islet regulatory landscape and provided novel insight into the properties of functional cis-regulatory variation.
Supervisor: Ferrer, Jorge Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral