Discovering metabolic disease gene interactions by correlated effects on cellular morphology.
Mol Metab
; 24: 108-119, 2019 06.
Article
em En
| MEDLINE
| ID: mdl-30940487
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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Adipócitos
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Diabetes Mellitus
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Adipogenia
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Redes Reguladoras de Genes
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Mapas de Interação de Proteínas
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos