Figure 4.
DHODH inhibition upregulates a transcriptional signature of oxidative phosphorylation. (A) Bubble dot plot depicting the GSEA NES for top hallmark gene sets enriched in the genome-wide transcriptional changes induced by BRQ treatment over 24 hours in Jurkat cells. Hallmark gene sets are presented as bubble dots. The dot size depicts the number of differentially expressed genes that are within the specified hallmark pathway. The dot color depicts the significance range of the P value. Significance cutoffs for GSEA: |NES| > 1.3, -log10(P value) > 1, and FDR < 0.25. (B) Schematic representation of the electron transport chain in the inner mitochondrial membrane and the location of DHODH. Highlighted are 14 genes and their relative positions within the electron transport chain, which were among the leading-edge genes driving the oxidative phosphorylation signature in Jurkat cells treated with BRQ. Additionally shown is a heat map depicting the log2(TPM + 1) expression for the replicate samples treated with BRQ vs dimethyl sulfoxide on the hallmark oxidative phosphorylation genes. Genes are ranked based on the log2 fold-change in expression induced by BRQ. Top 25 up-regulated leading-edge genes are annotated. (C) The oxygen consumption rate (OCR) was measured using the Seahorse XF Cell Mito Stress Test assay. Cells were treated with BRQ for 24 hours preceding the assay. OCR was measured over 74 minutes. This experiment was performed twice. (D) Jurkat cells were treated with 1 μM BRQ over a time course. Cells were then stained with MitoTracker Deep Red and fluorescence was measured using flow cytometry. This experiment was performed 3 times. (E) Jurkat and PF-382 cells were treated with 1 μM BRQ for 24 hours. Cells were then stained with tetramethyl rhodamine methyl ester (TMRM) and fluorescence was measured using flow cytometry. This experiment was performed 4 times. APC, allophycocyanin; MFI, mean fluorescence intensity; PE, phycoerythrin. Panel B was adapted from “Electron Transport Chain,” by BioRender.com (2020).

DHODH inhibition upregulates a transcriptional signature of oxidative phosphorylation. (A) Bubble dot plot depicting the GSEA NES for top hallmark gene sets enriched in the genome-wide transcriptional changes induced by BRQ treatment over 24 hours in Jurkat cells. Hallmark gene sets are presented as bubble dots. The dot size depicts the number of differentially expressed genes that are within the specified hallmark pathway. The dot color depicts the significance range of the P value. Significance cutoffs for GSEA: |NES| > 1.3, -log10(P value) > 1, and FDR < 0.25. (B) Schematic representation of the electron transport chain in the inner mitochondrial membrane and the location of DHODH. Highlighted are 14 genes and their relative positions within the electron transport chain, which were among the leading-edge genes driving the oxidative phosphorylation signature in Jurkat cells treated with BRQ. Additionally shown is a heat map depicting the log2(TPM + 1) expression for the replicate samples treated with BRQ vs dimethyl sulfoxide on the hallmark oxidative phosphorylation genes. Genes are ranked based on the log2 fold-change in expression induced by BRQ. Top 25 up-regulated leading-edge genes are annotated. (C) The oxygen consumption rate (OCR) was measured using the Seahorse XF Cell Mito Stress Test assay. Cells were treated with BRQ for 24 hours preceding the assay. OCR was measured over 74 minutes. This experiment was performed twice. (D) Jurkat cells were treated with 1 μM BRQ over a time course. Cells were then stained with MitoTracker Deep Red and fluorescence was measured using flow cytometry. This experiment was performed 3 times. (E) Jurkat and PF-382 cells were treated with 1 μM BRQ for 24 hours. Cells were then stained with tetramethyl rhodamine methyl ester (TMRM) and fluorescence was measured using flow cytometry. This experiment was performed 4 times. APC, allophycocyanin; MFI, mean fluorescence intensity; PE, phycoerythrin. Panel B was adapted from “Electron Transport Chain,” by BioRender.com (2020).

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