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Insights into T2D regulatory networks from 3D chromatin maps and genome editing

IBCS seminar

Dr Ines Cebola Imperial College London Faculty of Medicine

Event details


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.
Recently, 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 beta cell line EndoC-bH3, demonstrating that the detected enhancer-promoter interactions reflect functional chromatin interactions in human islets.
Our studies have revealed that 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.
This study has been recently published in Nature Genetics.

Bio: Inês Cebola is a molecular biologist with a strong interest in understanding how noncoding sequences affect disease risk. She spent the past 8 years in Prof Jorge Ferrer’s team, in which she investigated how sequence variation in pancreatic transcriptional enhancers can contribute to both rare and common forms of diabetes (Weedon et al NG 2014; Cebola el al NCB 2015; Miguel-Escalada et al NG 2019). In the past few years, she applied genome editing in pancreatic beta cells to investigate 3D chromatin interactions between enhancers and their target genes. Dr. Cebola has been recently appointed as Lecturer in Epigenomics in Imperial College London and holds funding from the Accelerating Medicines Partnership for Type 2 Diabetes to investigate genetic mechanisms that affect liver cell function. She has been awarded this year's Science Lecture Prize by the Society for Endocrinology.