|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Jiao, 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|
|Date Published||2019 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 Journal||Mol Metab|
|PubMed Central ID||PMC6531784|
|Grant List||K08 DK102877 / DK / NIDDK NIH HHS / United States |
MR/L002620/1 / / Medical Research Council / United Kingdom