Project description:Desulfotomaculum reducens is the first Gram-positive sulfate- and metal- reducing bacterium for which the transcriptomic response to uranium exposure has been evaluated. The genes upregulated during fermentative growth in the presence of U(VI) as compared to its absence included those encoding for proteins involved in respiration such as NADH quinone oxidoreductase and heterodisulfide reductase. This finding suggested that electrons were shuttled to the electron transport chain during fermentation which points to the reduction of U(VI) as a metabolic process. While U(IV) is typically insoluble and readily removable by filtration, U(IV) produced during active growth was not retained by a 0.2 µm pore size filter and filtration was not sufficient to differentiate between U(VI) and U(IV). In addition, genes involved in iron homeostasis were upregulated in the presence of uranium, which was consistent with the upregulation of genes involved in c-type cytochrome biogenesis. Despite the upregulation of cytochrome biosynthesis genes, the sole c-type cytochrome encoded in the genome was not differentially expressed. Finally, genes encoding metal efflux pumps were also upregulated indicating the toxic nature of uranium. Analysis of the time-dependent gene expression showed that sporulation was the dominant process at the early stationary phase and that the presence of U at that stage did not impact expression. This data set is a time course comparing sulfate and uranium reduction with fermentative growth.
Project description:Desulfotomaculum reducens is the first Gram-positive sulfate- and metal- reducing bacterium for which the transcriptomic response to uranium exposure has been evaluated. The genes upregulated during fermentative growth in the presence of U(VI) as compared to its absence included those encoding for proteins involved in respiration such as NADH quinone oxidoreductase and heterodisulfide reductase. This finding suggested that electrons were shuttled to the electron transport chain during fermentation which points to the reduction of U(VI) as a metabolic process. While U(IV) is typically insoluble and readily removable by filtration, U(IV) produced during active growth was not retained by a 0.2 µm pore size filter and filtration was not sufficient to differentiate between U(VI) and U(IV). In addition, genes involved in iron homeostasis were upregulated in the presence of uranium, which was consistent with the upregulation of genes involved in c-type cytochrome biogenesis. Despite the upregulation of cytochrome biosynthesis genes, the sole c-type cytochrome encoded in the genome was not differentially expressed. Finally, genes encoding metal efflux pumps were also upregulated indicating the toxic nature of uranium. Analysis of the time-dependent gene expression showed that sporulation was the dominant process at the early stationary phase and that the presence of U at that stage did not impact expression.
Project description:Recent development of new immune checkpoint inhibitors has been particularly successfully in cancer treatment, but still the majority patients fail to benefit. Converting resistant tumors to immunotherapy sensitivity will provide a significant improvement in patient outcome. Here we identify Mi-2β as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Genetically engineered mouse melanoma studies indicate that loss of Mi-2β rescued the immune response to immunotherapy in vivo. Mechanistically, ATAC-seq indicate that Mi-2β controlled the accessibility of IFN-γ-stimulated genes (ISGs). Mi-2β bound to EZH2 and promote K510 methylation of EZH2 and subsequently activate the trimethylation of H3K27 to inhibit the transcription of ISGs. Finally, we develop an Mi-2β-targeted inhibitor, Z36-MP5, which targeted inhibition of Mi-2β ATPase activity and recovered ISG transcription. Consequently, Z36-MP5 efficiently induce a response to immunotherapy in otherwise resistant melanomas. Our work provides a potential therapeutic strategy to convert immunotherapy resistant melanomas to sensitive ones.
Project description:Neuroblastoma (NB) is a common pediatric malignancy tumor with poor outcome. Recent studies show that MDM2 protein inhibitors are promising anti-cancer agents. MI-773 is a novel and specific antagonist of MDM2 and the molecular mechanisms of MI-773 in neuroblastoma are still unclear. In this study, we used microarrays to analyze the global change in gene expression as a result of MI-773 treatment in the human neuroblastoma cell line SH-SY5Y.