Unravelling of new type 2 diabetes genes with 3D chromatin topology analysis and CRISPR-Cas9 perturbations
Year: 2019
Type: conference-abstract
Abstract: Genome-wide association studies have identified nearly 250 loci carrying genetic variants associated with type 2 diabetes (T2D) susceptibility, which are often located within pancreatic islet transcriptional enhancers. Due to the complex nature of transcriptional enhancers, assigning risk variants to true disease susceptibility effector genes has remained a challenge. In this study, we applied promoter capture Hi-C to create a genome-wide map of promoter-enhancer interactions in adult human pancreatic islets. We then set out to investigate which genes are regulated by enhancers carrying T2D risk variants, observing that T2D variants often interact with more than one gene, and that, unlike what has been assumed until now, the nearest genes are not always the true targets of T2D susceptibility variants. We validated our in silico predictions by applying CRISPR-Cas9-based methods to perturb T2D enhancers in the human pancreatic ß cell line EndoC-ßH3, demonstrating that the detected enhancer-promoter interactions reflect functional chromatin interactions in human islets. This study reveals 3D chromatin architecture analysis coupled with genome editing as a powerful framework for interpretation of T2D genetic association signals. Furthermore, the results shed light into unexpected regulatory links that may affected by T2D susceptibility variants, bringing to our attention new players in T2D aetiology.
Source: Endocrine Abstracts
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2982774267