To better understand how TFE3 fusion proteins drive transformation in tRCC, we performed gain and loss of function experiments complemented by multi-omics approaches to profile genome occupancy of TFE3 fusions, identify active cis-regulatory elements and characterize the gene expression programs under their control in model cell lines and human tumors. The gene discussed is TFE3; the disease is renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusions.