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Christina Schmidt, Ariane Mora, Lorea Valcarcel, Laura Tronci, Efterpi Nikitopoulou, Ming Yang, Sabrina Rossie, Alexander von Kriegsheim, Mikael Boden and Christian Frezza (Box 197 Cambridge Biomedical Campus, Hutchsion/MRC Research Centre)
Fumarate Hydratase (FH) is an enzyme of the TCA cycle whose loss leads to renal cancer. The loss of FH results in profound metabolic changes including the accumulation of fumarate, which induces changes in DNA methylation, transcription, and translation that contributes to tumorigenesis. Yet, at what level this multi-layer reprogramming is orchestrated is unclear. Here, we generated FH-deficient human renal epithelial cell lines using CRISPR/Cas9-based genome editing, and applied proteomics, metabolomics, and transcriptomics approaches to investigate how the loss of FH alters these cellular layers. We confirmed that this model faithfully recapitulates the biochemical and phenotypic markers of FH-deficiency as previously reported. Next, we developed a novel multi-omics tool, SiRCle (Signature Regulatory Clusters) to disentangle this interconnected network of signalling cascades. Using SiRCle, we extracted independent clusters of genes with increased/decreased gene expression that are regulated at the level of DNA methylation, transcription, and/or translation, and identified clusters that may drive the FH loss phenotype.