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Discovering metabolic disease gene interactions by correlated effects on cellular morphology

Yang Jiao1, Umer Ahmed1, M F Michelle Sim2

  • 1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Molecular Metabolism
|April 4, 2019
PubMed
Abstract

Insights

Researchers identified key genes influencing fat cell development and insulin resistance. This study reveals new interactions for understanding Type 2 Diabetes (T2D) and metabolic diseases.

Area of Science:

  • Metabolic disease research
  • Adipocyte biology
  • Genetics and genomics

Background:

  • Impaired peripheral fat expansion is linked to insulin resistance and Type 2 Diabetes (T2D).
  • Understanding gene function in adipocyte differentiation is crucial for metabolic health.

Purpose of the Study:

  • To identify novel disease-gene interactions in adipocyte differentiation.
  • To investigate the role of T2D and obesity-associated genes in fat cell development.

Main Methods:

  • Genes associated with T2D, adiposity, and insulin resistance were ranked by expression in human adipocytes.
  • CRISPR/Cas9 was used to ablate the top 125 genes in pre-adipocytes.
  • High-content microscopy and image analysis quantified cellular phenotypes during differentiation.

Main Results:

  • Over 10^7 morphometric measurements revealed 14 genes associated with decreased lipid accumulation.
  • These genes were enriched for known lipodystrophy genes.
  • Novel protein-protein and gene regulatory interactions were validated for BSCL2 and AGPAT2 with PLIN1 and CEBPA.

Conclusions:

  • A morphometric approach in adipocytes can elucidate cellular mechanisms underlying metabolic disease loci.
  • This method allows for the mechanistic study of numerous unknown metabolic disease genes.
Keywords:
Functional genomicsGene discoveryGenetic screenHigh content imagingInsulin resistanceLipodystrophyMetabolic syndromeType 2 diabetes

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