ABSTRACT: We identified around 7000 proteins of which 6500 have been used for identification of novel pathways involved in NB pathogenesis and for investigation of potential MYC related biomarkers.
Project description:In order to investigate the effect of MondoA loss on the expression of Myc-dependent genes, we performed a microarray analysis from RNAs isolated from TET21N cells expressing either control (siControl) or MondoA (siMondoA) siRNAs either with (NT) or without (Doxy) induced N-Myc expression. TET21N cells were grown in medium with either Doxy (Myc-Off) or No Treatment (Myc-On), then transiently transfected with either non-specific siRNA or MondoA siRNA in replicates. Cells were then lysed and RNA isolated.
Project description:Soybean (Glycine max) seeds are an important source of seed storage compounds, including protein, oil, and sugar used for food, feed, chemical, and biofuel production. We assessed detailed temporal transcriptional and metabolic changes in developing soybean embryos to gain a systems biology view of developmental and metabolic changes and to identify potential targets for metabolic engineering. Two major developmental and metabolic transitions were captured enabling identification of potential metabolic engineering targets specific to seed filling and to desiccation. The first transition involved a switch between different types of metabolism in dividing and elongating cells. The second transition involved the onset of maturation and desiccation tolerance during seed filling and a switch from photoheterotrophic to heterotrophic metabolism. Clustering analyses of metabolite and transcript data revealed clusters of functionally related metabolites and transcripts active in these different developmental and metabolic programs. The gene clusters provide a resource to generate predictions about the associations and interactions of unknown regulators with their targets based on “guilt-by-association” relationships. The inferred regulators also represent potential targets for future metabolic engineering of relevant pathways and steps in central carbon and nitrogen metabolism in soybean embryos and drought and desiccation tolerance in plants. SUBMITTER_CITATION: Biology 2013, 2(4), 1311-1337; doi:10.3390/biology2041311 Changes in RNA Splicing in Developing Soybean (Glycine max) Embryos Delasa Aghamirzaie, Mahdi Nabiyouni, Yihui Fang, Curtis Klumas, Lenwood S. Heath, Ruth Grene and Eva Collakova SUBMITTER_CITATION: Metabolites 2013, 3(2), 347-372; doi:10.3390/metabo3020347 Metabolic and Transcriptional Reprogramming in Developing Soybean (Glycine max) Embryos Eva Collakova, Delasa Aghamirzaie, Yihui Fang, Curtis Klumas, Farzaneh Tabataba, Akshay Kakumanu, Elijah Myers, Lenwood S. Heath and Ruth Grene Total mRNA profiles of 10 time course samples of Soybean developing embryos with three replicates per sample were generated by deep sequencing, using Illumina HiSeq 2000
Project description:Dysregulated pre-mRNA splicing and metabolism are two hallmarks of MYC-driven cancers. Pharmacological inhibition of both processes has been extensively investigated as potential therapeutic avenues in preclinical and clinical studies. However, how pre-mRNA splicing and metabolism are orchestrated in response to oncogenic stress and therapies is poorly understood. Here, we demonstrate that Jumonji Domain Containing 6, Arginine Demethylase and Lysine Hydroxylase, or JMJD6, acts as a hub connecting splicing and metabolism in MYC-driven neuroblastoma. JMJD6 cooperates with MYC in cellular transformation by physically interacting with RNA binding proteins involved in pre-mRNA splicing and protein homeostasis. Notably, JMJD6 controls the alternative splicing of two isoforms of glutaminase (GLS), namely kidney-type glutaminase (KGA) and glutaminase C (GAC), which are rate-limiting enzymes of glutaminolysis in the central carbon metabolism in neuroblastoma. Further, we show that JMJD6 is correlated with the anti-cancer activity of indisulam, a “molecular glue” that degrades splicing factor RBM39, which complexes with JMJD6. The indisulam-mediated cancer cell killing is at least partly dependent on the glutamine-related metabolic pathway mediated by JMJD6. Our findings reveal a cancer-promoting metabolic program is coupled with alternative pre-mRNA splicing through JMJD6, providing a rationale to target JMJD6 as a therapeutic avenue for treating MYC-driven cancers.
Project description:Soybean (Glycine max) seeds are an important source of seed storage compounds, including protein, oil, and sugar used for food, feed, chemical, and biofuel production. We assessed detailed temporal transcriptional and metabolic changes in developing soybean embryos to gain a systems biology view of developmental and metabolic changes and to identify potential targets for metabolic engineering. Two major developmental and metabolic transitions were captured enabling identification of potential metabolic engineering targets specific to seed filling and to desiccation. The first transition involved a switch between different types of metabolism in dividing and elongating cells. The second transition involved the onset of maturation and desiccation tolerance during seed filling and a switch from photoheterotrophic to heterotrophic metabolism. Clustering analyses of metabolite and transcript data revealed clusters of functionally related metabolites and transcripts active in these different developmental and metabolic programs. The gene clusters provide a resource to generate predictions about the associations and interactions of unknown regulators with their targets based on guilt-by-association relationships. The inferred regulators also represent potential targets for future metabolic engineering of relevant pathways and steps in central carbon and nitrogen metabolism in soybean embryos and drought and desiccation tolerance in plants.
Project description:Influenza infection is a worldwide health and financial burden posing a significant risk to the immune-compromised, obese, diabetic, elderly, and pediatric populations. We identified increases in glucose metabolism in the lungs of pediatric patients infected with respiratory pathogens. Using quantitative mass spectrometry we found metabolic changes occurring after influenza infection in primary human respiratory cells, and validated infection associate increases in c-Myc, glycolysis, and glutaminolysis. We confirmed these findings with a metabolic drug screen and high throughput titering that identified the PI3K/mTOR inhibitor BEZ235 as a regulator of infectious virus production. BEZ235 treatment ablated the transient induction of c-Myc, restored PI3K/mTOR pathway homeostasis measured by 4E-BP1 and p85 phosphorylation, and reversed infection-induced changes in glucose and glutamine metabolism. Importantly, BEZ235 reduced infectious progeny but had no effect on viral entry or the early stages of viral replication. In a lethal infection model, BEZ235 significantly increased survival while reducing viral titer and respiratory distress. Here we show metabolic reprogramming of host cells by influenza virus exposes targets for therapeutic intervention.
Project description:In order to investigate the effect of MondoA loss on the expression of Myc-dependent genes, we performed a microarray analysis from RNAs isolated from TET21N cells expressing either control (siControl) or MondoA (siMondoA) siRNAs either with (NT) or without (Doxy) induced N-Myc expression.
Project description:BACKGROUND: The diabetic macroangiopathy includes coronary heart disease, cerebrovascular disease and peripheral artery disease. Diabetic macroangiopathy is the main cause of death in diabetic patients. The exact pathogenesis of diabetic macroangiopathy is still not completely clear. METHODS: Single-cell transcriptome, spatial transcriptome, and spatial metabolome sequencing were performed on specimens of the anterior tibial artery from 11 amputated patients for visualization and data analysis through bioinformatics. RESULTS: This study reveals the gene-metabolic network in metabolic reprogramming and calcification characteristics in diabetic macrovasculature. Tissue specificity was found in some metabolic pathways. Alpha-linolenic acid metabolism and linoleic acid metabolism were characteristically enriched in the arteriae externa, and folate biosynthesis was characteristically expressed in calcification region. O-glycan biosynthesis, and primary bile acid biosynthesis are enriched in plaques. The calcification area mainly expresses COL1A2 COL6A2 FN1, MIF, SPP1, TNC as ligands to adjust and control media and plaque. The presence of nuclear enrichment related lesion changes around calcification resulted in activation of chemokine function, erk1/2 function and phenylalanine pathway. CONCLUSIONS: This study is the first to construct a spatial gene-metabolic map of complete blood vessels, which provides a basis for the subsequent exploration of the mechanism and clinical transformation of diabetic macrovascular disease.
Project description:BACKGROUND: The diabetic macroangiopathy includes coronary heart disease, cerebrovascular disease and peripheral artery disease. Diabetic macroangiopathy is the main cause of death in diabetic patients. The exact pathogenesis of diabetic macroangiopathy is still not completely clear. METHODS: Single-cell transcriptome, spatial transcriptome, and spatial metabolome sequencing were performed on specimens of the anterior tibial artery from 11 amputated patients for visualization and data analysis through bioinformatics. RESULTS: This study reveals the gene-metabolic network in metabolic reprogramming and calcification characteristics in diabetic macrovasculature. Tissue specificity was found in some metabolic pathways. Alpha-linolenic acid metabolism and linoleic acid metabolism were characteristically enriched in the arteriae externa, and folate biosynthesis was characteristically expressed in calcification region. O-glycan biosynthesis, and primary bile acid biosynthesis are enriched in plaques. The calcification area mainly expresses COL1A2 COL6A2 FN1, MIF, SPP1, TNC as ligands to adjust and control media and plaque. The presence of nuclear enrichment related lesion changes around calcification resulted in activation of chemokine function, erk1/2 function and phenylalanine pathway. CONCLUSIONS: This study is the first to construct a spatial gene-metabolic map of complete blood vessels, which provides a basis for the subsequent exploration of the mechanism and clinical transformation of diabetic macrovascular disease.