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A genome-wide CRISPR screen identifies CALCOCO2 as a regulator of beta cell function influencing type 2 diabetes risk

Antje K Rottner1, Yingying Ye2, Elena Navarro-Guerrero3

  • 1Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

Nature Genetics
|December 21, 2022
PubMed

Insights

This study used CRISPR screening in beta cells to find genes affecting type 2 diabetes (T2D). Researchers identified CALCOCO2 as a key gene, linking its function to insulin secretion and T2D risk.

Area of Science:

  • Genetics
  • Cell Biology
  • Metabolic Diseases

Background:

  • Identifying causal genes for complex diseases like type 2 diabetes (T2D) is challenging.
  • Many T2D genetic signals impact pancreatic beta cell function.

Purpose of the Study:

  • To identify genes and pathways regulating pancreatic beta cell function relevant to T2D.
  • To experimentally validate candidate T2D genes using a functional genomics approach.

Main Methods:

  • Genome-wide pooled CRISPR loss-of-function screen in a human pancreatic beta cell line.
  • Assessed regulation of insulin content as a readout of beta cell function.
  • Integrated screening data with genetic and genomic datasets.

Main Results:

  • Identified 580 genes influencing insulin content in beta cells.
  • Provided experimental support for 20 candidate T2D effector transcripts.
  • Demonstrated that loss of CALCOCO2 impairs beta cell function, affecting mitochondria, insulin granules, and autophagy, and is linked to T2D variants and altered insulin secretion.

Conclusions:

  • Cellular screens can enhance multi-omic studies for understanding complex disease mechanisms.
  • Provided evidence for causal roles of specific genes, including CALCOCO2, at genome-wide association study loci for T2D.

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