Discovering cellular programs of intrinsic and extrinsic drivers of metabolic traits using LipocyteProfiler

Strobel, S.; Laber, S.; Mercader, J. M.; Dashti, H.; Ainbinder, A.; Honecker, J.; Garborcauskas, G.; Stirling, D. R.; Leong, A.; Figueroa, K.; Sinnott-Armstrong, N.; Kost-Alimova, M.; Deodato, G.; Harney, A.; Way, G. P.; Saadat, A.; Harken, S.; Reibe-Pal, S.; Ebert, H.; Zhang, Y.; Calabuig, V.; McGonagle, E.; Stefek, A.; Dupuis, J.; Cimini, B.; Hauner, H.; Udler, M. S.; Carpenter, A. E.; Florez, J. C.; Lindgren, C. M.; Jacobs, S. B.; Claussnitzer, M.

doi:10.1101/2021.07.17.452050

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bioRxiv · 10.1101/2021.07.17.452050

Discovering cellular programs of intrinsic and extrinsic drivers of metabolic traits using LipocyteProfiler

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Abstract

A primary obstacle in translating genetics and genomics data into therapeutic strategies is elucidating the cellular programs affected by genetic variants and genes associated with human diseases. Broadly applicable high-throughput, unbiased assays offer a path to rapidly characterize gene and variant function and thus illuminate disease mechanisms. Here, we report LipocyteProfiler, an unbiased high-throughput, high-content microscopy assay that is amenable to large-scale morphological and cellular profiling of lipid-accumulating cell types. We apply LipocyteProfiler to adipocytes and hepatocytes and demonstrate its ability to survey diverse cellular mechanisms by generating rich context-, and process-specific morphological and cellular profiles. We then use LipocyteProfiler to identify known and novel cellular programs altered by polygenic risk of metabolic disease, including insulin resistance, waist-to-hip ratio and the polygenic contribution to lipodystrophy. LipocyteProfiler paves the way for large-scale forward and reverse phenotypic profiling in lipid-storing cells, and provides a framework for the unbiased identification of causal relationships between genetic variants and cellular programs relevant to human disease.

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Strobel, S., Laber, S., Mercader, J. M., Dashti, H., Ainbinder, A., Honecker, J., Garborcauskas, G., Stirling, D. R., Leong, A., Figueroa, K., Sinnott-Armstrong, N., Kost-Alimova, M., Deodato, G., Harney, A., Way, G. P., Saadat, A., Harken, S., Reibe-Pal, S., Ebert, H., Zhang, Y., Calabuig, V., McGonagle, E., Stefek, A., Dupuis, J., Cimini, B., Hauner, H., Udler, M. S., Carpenter, A. E., Florez, J. C., Lindgren, C. M., Jacobs, S. B., Claussnitzer, M.. 2021-07-19. Discovering cellular programs of intrinsic and extrinsic drivers of metabolic traits using LipocyteProfiler. https://doi.org/10.1101/2021.07.17.452050

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