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Discovering metabolic disease gene interactions by correlated effects on cellular morphology.
Jiao, Yang; Ahmed, Umer; Sim, M F 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.
Afiliação
  • Jiao Y; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Ahmed U; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Sim MFM; University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
  • Bejar A; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Zhang X; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Talukder MMU; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
  • Rice R; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Flannick J; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Podgornaia AI; Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, MA 02115, USA.
  • Reilly DF; Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, MA 02115, USA.
  • Engreitz JM; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Kost-Alimova M; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Hartland K; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Mercader JM; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Georges S; Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, MA 02115, USA.
  • Wagh V; Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, MA 02115, USA.
  • Tadin-Strapps M; Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, MA 02115, USA.
  • Doench JG; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Edwardson JM; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
  • Rochford JJ; University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK; Rowett Institute and the Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
  • Rosen ED; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Endocrinology, Diabetes and Obesity, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Harvard Medical School, Department of Genetics, Boston, MA 02215, USA.
  • Majithia AR; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: amajithia@ucsd.edu.
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Adipócitos / Diabetes Mellitus / Adipogenia / Redes Reguladoras de Genes / Mapas de Interação de Proteínas Idioma: En Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Adipócitos / Diabetes Mellitus / Adipogenia / Redes Reguladoras de Genes / Mapas de Interação de Proteínas Idioma: En Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos