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Integration between Notch- and hypoxia-induced transcriptomes

ABSTRACT: Background: Interaction between key signaling mechanisms is important to generate the diversity in signaling output required for proper control of cellular differentiation and function, although the molecular manifestations of such cross-talk are only partially understood. Notch signaling and the cellular response to hypoxia intersect at different points in the signaling cascades, and in this report we analyze the consequences of this cross-talk at the transcriptome level. Results: Mouse ES cells were subjected to various combinations of hypoxia and/or activated Notch signaling, and the transcriptome changes could be grouped into different categories, reflecting various modes of hypoxia and Notch signaling integration. Two principal categories of novel Notch- and hypoxia-induced genes were identified: i) a larger set of genes induced by one pathway and not significantly affected by the activity status of the other pathway; and ii) a smaller set of genes co-regulated by Notch and hypoxia. In the latter category, we identified genes that were induced by hypoxia and the expression of which was enhanced by active Notch signaling. In addition, a number of genes were induced by Notch and hypoxia independently, and a final category of genes required simultaneous activation of Notch and hypoxia to be significantly induced. Several of the hypoxia- and Notch-induced genes were found to be upregulated in various forms of cancer. Conclusions: We identify novel Notch and hypoxia downstream genes and genes co-regulated by the two pathways, providing a molecular platform to better understand the intersection between the two signaling cascades in normal development and cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE19074 | GEO | 2009/12/31

SECONDARY ACCESSION(S): PRJNA120477

REPOSITORIES: GEO

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Project description:Sivakumar2011 - Notch Signaling Pathway Notch is a transmembrane receptor that mediates local cell-cell communication and coordinates a signaling cascade. It plays a key role in modulating cell fate decisions throughout the development of invertebrate and vertebrate species and the misregulation leads to a number of human diseases. References: Notch signaling: from the outside in. Notch signaling in hematopoiesis and early lymphocyte development. An overview of the Notch signalling pathway. Notch and cancer: best to avoid the ups and downs. Notch signaling: control of cell communication and cell fate. This model is described in the article: A systems biology approach to model neural stem cell regulation by notch, shh, wnt, and EGF signaling pathways. Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S. Omics: a Journal of Integrative Biology. 2011; 15(10):729-737 Abstract: The Notch, Sonic Hedgehog (Shh), Wnt, and EGF pathways have long been known to influence cell fate specification in the developing nervous system. Here we attempted to evaluate the contemporary knowledge about neural stem cell differentiation promoted by various drug-based regulations through a systems biology approach. Our model showed the phenomenon of DAPT-mediated antagonism of Enhancer of split [E(spl)] genes and enhancement of Shh target genes by a SAG agonist that were effectively demonstrated computationally and were consistent with experimental studies. However, in the case of model simulation of Wnt and EGF pathways, the model network did not supply any concurrent results with experimental data despite the fact that drugs were added at the appropriate positions. This paves insight into the potential of crosstalks between pathways considered in our study. Therefore, we manually developed a map of signaling crosstalk, which included the species connected by representatives from Notch, Shh, Wnt, and EGF pathways and highlighted the regulation of a single target gene, Hes-1, based on drug-induced simulations. These simulations provided results that matched with experimental studies. Therefore, these signaling crosstalk models complement as a tool toward the discovery of novel regulatory processes involved in neural stem cell maintenance, proliferation, and differentiation during mammalian central nervous system development. To our knowledge, this is the first report of a simple crosstalk map that highlights the differential regulation of neural stem cell differentiation and underscores the flow of positive and negative regulatory signals modulated by drugs. This model is hosted on BioModels Database and identified by: BIOMD0000000396. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:The hippocampal proteins obtained from both exercised (moderate-intensity running for 6 weeks) and sedentary mice were separately analyzed for Liquid chromatography–tandem mass spectrometry (LC-MS/MS) identification with three replications. Acetylome data identified 3876 acetyl sites and 1764 acetylated proteins, which constituted 31% of the whole hippocampal proteome (totally 5725 proteins identified). In addition, 1305 proteins with 2769 acetyl sites were quantified. When defining the cutoffs for the fold change in abundance of 1.5 and P value < 0.05, 272 acetyl sites on 252 proteins were differentially regulated between exercise and control mice. Analysis of the subcellular localization showed that these differentially acetylated proteins (DAPs) exert different functions in multiple compartments, including the cytoplasm, mitochondria, nucleus and plasma membrane. The 19 up-regulated acetylated proteins mainly resided in mitochondria, while the 253 down-regulated DAPs were most abundant in cytoplasm, and the annotation of molecular functions were significantly enriched in catalytic activity and binding, respectively. Gene Ontology (GO) analysis showed that DAPs were primarily correlated with cytoskeleton, myelin sheath and axons in the cellular component category; and actin cytoskeleton organization, regulation of protein polymerization or depolymerization, and hexose/glucose metabolic process were significantly enriched in the biological process category. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that DAPs were involved in central carbon metabolism, neurodegeneration diseases, synapses, and various signaling pathways. Among them, chronic exercise induced significant alterations in phototransduction, carbon-related metabolism (carbohydrate digestion and absorption, glycolysis/gluconeogenesis, fructose and mannose metabolism, and pyruvate metabolism) and Hippo signaling pathway. Meanwhile, 21 proteins were significantly expressed, which were enriched in the pathway of complement and coagulation cascades.

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Integration between Notch- and hypoxia-induced transcriptomes

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