A genome-wide CRISPR screen maps endogenous regulators of PPARG gene expression in bladder cancer

Davide Tortora; Morgan E Roberts; Gunjan Kumar; Sudha S Kotapalli; Elie Ritch; Joshua M Scurll; Brian McConeghy; Sunita Sinha; Alexander W Wyatt; Peter C Black; Mads Daugaard

doi:10.1016/j.isci.2023.106525

A genome-wide CRISPR screen maps endogenous regulators of PPARG gene expression in bladder cancer

iScience. 2023 Mar 30;26(5):106525. doi: 10.1016/j.isci.2023.106525. eCollection 2023 May 19.

Affiliations

¹ Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
² Sequencing and Bioinformatics Consortium, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor central in the regulation of key cellular processes including cell metabolism, tissue differentiation, and regulation of the immune system. PPARγ is required for normal differentiation of the urothelium and is thought to be an essential driver of the luminal subtype of bladder cancer. However, the molecular components that regulate PPARG gene expression in bladder cancer remain unclear. Here, we developed an endogenous PPARG reporter system in luminal bladder cancer cells and performed genome-wide CRISPR knockout screening to identify bona fide regulators of PPARG gene expression. Functional validation of the dataset confirmed GATA3, SPT6, and the cohesin complex components SMC1A, and RAD21, as permissive upstream positive regulators of PPARG gene expression in luminal bladder cancer. In summary, this work provides a resource and biological insights to aid our understanding of PPARG regulation in bladder cancer.

Keywords: Biological sciences; Cancer; Molecular biology; Molecular mechanism of gene regulation.