The urothelial gene regulatory network: understanding biology to improve bladder cancer management.

The urothelium is a stratified epithelium composed of basal cells, one or more layers of intermediate cells, and an upper layer of differentiated umbrella cells. Most bladder cancers (BLCA) are urothelial carcinomas. Loss of urothelial lineage fidelity results in altered differentiation, highlighted by the taxonomic classification into basal and luminal tumors. There is a need to better understand the urothelial transcriptional networks. To systematically identify transcription factors (TFs) relevant for urothelial identity, we defined highly expressed TFs in normal human bladder using RNA-Seq data and inferred their genomic binding using ATAC-Seq data. To focus on epithelial TFs, we analyzed RNA-Seq data from patient-derived organoids recapitulating features of basal/luminal tumors. We classified TFs as "luminal-enriched", "basal-enriched" or "common" according to expression in organoids. We validated our classification by differential gene expression analysis in Luminal Papillary vs. Basal/Squamous tumors. Genomic analyses revealed well-known TFs associated with luminal (e.g., PPARG, GATA3, FOXA1) and basal (e.g., TP63, TFAP2) phenotypes and novel candidates to play a role in urothelial differentiation or BLCA (e.g., MECOM, TBX3). We also identified TF families (e.g., KLFs, AP1, circadian clock, sex hormone receptors) for which there is suggestive evidence of their involvement in urothelial differentiation and/or BLCA. Genomic alterations in these TFs are associated with BLCA. We uncover a TF network involved in urothelial cell identity and BLCA. We identify novel candidate TFs involved in differentiation and cancer that provide opportunities for a better understanding of the underlying biology and therapeutic intervention.

Deciphering fruit sugar transport and metabolism from tolerant and sensitive tomato plants subjected to simulated field conditions.

In the current state of climate change, we must assume that abiotic stresses act together under natural field conditions, these will increase in the coming years. Therefore, in this report we investigated how sugar metabolism was affected under simulated field conditions, where plants faced high ambient temperatures and a low-quality water irrigation. Our studies were carried out on fruits of two tomato recombinant lines, a tolerant and a sensitive one exposed to the combination of heat and salinity. Two ripening stages (mature green and red ripe fruits) were used in our analyzes, where the gene expression levels of the main biosynthetic genes and transporters, enzymatic activities and compounds related to the synthesis, accumulation, and degradation of sugars in plants were analyzed. The tolerant line showed highly significant differences in red ripe fruits in comparison to the sensitive one under the simulated field conditions (35°C + 60 mM NaCl), with an overexpression of the genes SlFBP, SlSPS, SlSUS3, and SlNi. These expression patterns correlated with a higher activity of the enzymes FBP, SPS, SUS3, AI, and G6PDH, which resulted in the accumulation of fructose, glucose and UDP-glucose. Our results showed the advantage of using tomato recombinant lines for rescuing important traits, such as the resistance to some abiotic stresses, and for the identification of important molecular and metabolic markers that could be used to determine fruit quality in green or red maturity stages under detrimental environmental field conditions.