evanrosen

37 posts

Suraj Patel has received the American Gastroenterological Association Research Scholar award

This is a research career development award that provides funding for 3 years. Suraj has previously found that Interferon Regulatory Factor 3 (IRF3) plays an essential role in obesity-induced non-alcoholic fatty liver disease (NAFLD). Mice deficient in IRF3 (IRF3KO) are protected against steatosis and hepatic insulin resistance induced by high fat diet. Genome-wide transcriptional profiling of IRF3KO and wild-type mice on HFD revealed two candidate IRF3 target genes, Isg15 and Srebf1, mediating IRF3-induced hepatic steatosis and insulin resistance. The aims of this project are to identify the hepatic cell type(s) responsible for IRF3-mediated steatosis and IR in NAFLD, and define the role of ISG15 and SREBP1 in promoting IRF3-induced metabolic dysfunction. 

Congratulations on the grant Suraj!

 

 

Discovering metabolic disease gene interactions by correlated effects on cellular morphology

Yang Jiao, Umer Ahmed, M.F. Michelle Sim, Andrea Bejar, Xiaolan Zhang, M. Mesbah Uddin Talukder, Robert Rice, Jason Flannick, Anna I. Podgornaia, Dermot F. Reilly, Jesse M. Engreitz, Maria Kost-Alimova, Kate Hartland, Josep-Maria Mercader, Sara Georges, Vilas Wagh, Marija Tadin-Strapps, John G. Doench, J. Michael Edwardson, Justin J. Rochford, Evan D. Rosen, Amit R. Majithia

Objective: Impaired expansion of peripheral fat contributes to the pathogenesis of insulin resistance and Type 2 Diabetes (T2D). We aimed to
identify novel diseaseegene 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 proteine
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.

Mol Metab. 2019 Jun; 24: 108–119. https://doi.org/10.1016/j.molmet.2019.03.001. Epub 2019 Mar 13.

PubMed

PDF

 

New paper in Molecular Metabolism

This collaboration with Amit Majithia’s group at the Broad (now at UC San Diego) shows that high content image morphometric analysis can be used to predict molecular pathways in adipogenesis. Read more about it here!