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Discovering metabolic disease gene interactions by correlated effects on cellular morphology.

  • Author(s): Jiao, Yang
  • Ahmed, Umer
  • Sim, MF Michelle
  • Bejar, Andrea
  • Zhang, Xiaolan
  • Talukder, M Mesbah Uddin
  • Rice, Robert
  • Flannick, Jason
  • Podgornaia, Anna I
  • Reilly, Dermot F
  • Engreitz, Jesse M
  • Kost-Alimova, Maria
  • Hartland, Kate
  • Mercader, Josep-Maria
  • Georges, Sara
  • Wagh, Vilas
  • Tadin-Strapps, Marija
  • Doench, John G
  • Edwardson, J Michael
  • Rochford, Justin J
  • Rosen, Evan D
  • Majithia, Amit R
  • et al.
Abstract

OBJECTIVE:Impaired expansion of peripheral fat contributes to the pathogenesis of insulin resistance and Type 2 Diabetes (T2D). We aimed to identify novel disease-gene interactions during adipocyte differentiation. METHODS:Genes in disease-associated loci for T2D, adiposity and insulin resistance were ranked according to expression in human adipocytes. The top 125 genes were ablated in human pre-adipocytes via CRISPR/CAS9 and the resulting cellular phenotypes quantified during adipocyte differentiation with high-content microscopy and automated image analysis. Morphometric measurements were extracted from all images and used to construct morphologic profiles for each gene. RESULTS:Over 107 morphometric measurements were obtained. Clustering of the morphologic profiles accross all genes revealed a group of 14 genes characterized by decreased lipid accumulation, and enriched for known lipodystrophy genes. For two lipodystrophy genes, BSCL2 and AGPAT2, sub-clusters with PLIN1 and CEBPA identifed by morphological similarity were validated by independent experiments as novel protein-protein and gene regulatory interactions. CONCLUSIONS:A morphometric approach in adipocytes can resolve multiple cellular mechanisms for metabolic disease loci; this approach enables mechanistic interrogation of the hundreds of metabolic disease loci whose function still remains unknown.

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