Unravelling molecular mechanisms for type 2 diabetes using genetic and genomic approaches

There are now over 100 regions of the human genome which robustly influence the risk of developing type 2 diabetes (T2D). Each of these association signals provides an opportunity to understand the causal mechanisms driving T2D pathogenesis. Broad physiological characterisation of T2D-associated variants in humans has elucidated their role in regulation of glucose levels, insulin secretion and/or action, identifying pathways involved in T2D pathogenesis, and demonstrating that most impact primarily on beta-cell function rather than insulin sensitivity. However, until recently efforts to make more detailed statements about biological mechanisms have typically been thwarted by difficulties in defining the precise causal variant, the transcripts through which the signals exert their impact on diabetes risk on account of the vast majority of signals mapping to poorly-annotated intergenic sequence and limited availability of authentic cellular models for mechanistic studies. In recent years next-generation sequencing technology has fuelled advancements in high throughput methodologies to link genetic variants to regulatory annotation through cis-eQTL mapping, transcript annotation (chromatin state) and conformational structure (Capture-C). These advancements have coincided with breakthroughs in genome editing (CRISPR-cas 9) and the availability of authentic cellular models (human IPS cell derived beta-cells) providing for the first time the opportunity to work at genome scale to deliver molecular mechanisms for T2D.

The overall objective of this DPhil project is to elucidate the functional mechanisms whereby genetic variants shown to influence T2D predisposition exert their effects at the molecular, cellular and whole-body level.

The successful student will use transcriptomic data (RNA-seq, ATAC-seq, whole-genome bisulphite sequencing, Capture-C) from human islets generated by the Gloyn group to identify association signals for mechanistic studies in authentic human beta-cell models (EndoCBh1 and IPS cell dervied. The selection of the precise variant(s) and transcripts will dictate the specifics of the project but the approaches that are likely to be employed for downstream characterisation will include siRNA and CRISPR-cas 9 mediated gene knockdown in human primary islets, beta-cell and IPS cell lines with appropriate cellular characterisation. There is scope to design projects with both "wet" and "dry" components to provide training in computational biology as well as state-of-the art genome editing.

This work is expected to provide powerful insights into the pathophysiology of T2D that will support translational advances in disease management.