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Mol Metab DOI:10.1016/j.molmet.2019.03.001

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

Publication TypeJournal Article
Year of Publication2019
AuthorsJiao, Y, Ahmed, U, Sim, MFMichelle, Bejar, A, Zhang, X, M Talukder, MUddin, Rice, R, Flannick, J, Podgornaia, AI, Reilly, DF, Engreitz, JM, Kost-Alimova, M, Hartland, K, Mercader, J-M, Georges, S, Wagh, V, Tadin-Strapps, M, Doench, JG, J Edwardson, M, Rochford, JJ, Rosen, ED, Majithia, AR
JournalMol Metab
Date Published2019 06

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 10 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.


Alternate JournalMol Metab
PubMed ID30940487
PubMed Central IDPMC6531784
Grant ListK08 DK102877 / DK / NIDDK NIH HHS / United States
MR/L002620/1 / / Medical Research Council / United Kingdom