CRISPR-based genome editing in primary human pancreatic islet cells

Romina J. Bevacqua, Xiaoqing Dai, Jonathan Y. Lam, Xueying Gu, Mollie S. H. Friedlander, Krissie Tellez, Irene Miguel-Escalada, Silvia Bonàs-Guarch, Goutham Atla, Weichen Zhao, Seung Hyun Kim, Antonia A. Dominguez, Lei S. Qi, Jorge Ferrer, Patrick E. MacDonald and Seung K. Kim ()
Additional contact information
Romina J. Bevacqua: Stanford University School of Medicine
Xiaoqing Dai: University of Alberta
Jonathan Y. Lam: Stanford University School of Medicine
Xueying Gu: Stanford University School of Medicine
Mollie S. H. Friedlander: Stanford University School of Medicine
Krissie Tellez: Stanford University School of Medicine
Irene Miguel-Escalada: Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST)
Silvia Bonàs-Guarch: Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST)
Goutham Atla: Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST)
Weichen Zhao: Stanford University School of Medicine
Seung Hyun Kim: Stanford University School of Medicine
Antonia A. Dominguez: Stanford University
Lei S. Qi: Stanford University
Jorge Ferrer: Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST)
Patrick E. MacDonald: University of Alberta
Seung K. Kim: Stanford University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Gene targeting studies in primary human islets could advance our understanding of mechanisms driving diabetes pathogenesis. Here, we demonstrate successful genome editing in primary human islets using clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9). CRISPR-based targeting efficiently mutated protein-coding exons, resulting in acute loss of islet β-cell regulators, like the transcription factor PDX1 and the KATP channel subunit KIR6.2, accompanied by impaired β-cell regulation and function. CRISPR targeting of non-coding DNA harboring type 2 diabetes (T2D) risk variants revealed changes in ABCC8, SIX2 and SIX3 expression, and impaired β-cell function, thereby linking regulatory elements in these target genes to T2D genetic susceptibility. Advances here establish a paradigm for genetic studies in human islet cells, and reveal regulatory and genetic mechanisms linking non-coding variants to human diabetes risk.

Date: 2021
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DOI: 10.1038/s41467-021-22651-w

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