GAM: a web-service for integrated transcriptional and metabolic network analysis

Sergushichev, Alexey; Loboda, Alexander A.; Jha, Abhishek; Vincent, Emma E.; Driggers, Edward M.; Jones, Russell G.; Pearce, Edward J.; Artyomov, Maxim N.

doi:10.1093/nar/gkw266

Cited by 87 publications

(65 citation statements)

References 31 publications

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“…Analysis of metabolite data alone, or in combination with RNA-Seq data by a systems-based algorithm (Sergushichev et al, 2016), revealed widespread differences between WT and Trem2 −/− BMDMs in various metabolic pathways. Compared to WT BMDMs in optimal CSF1, Trem2 −/− BMDMs cultured under the same conditions exhibited: 1) a marked decrease of key intermediates in the synthesis of nucleotides (e.g.…”

Section: Resultsmentioning

confidence: 99%

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TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease

Ulland

Song

Huang

et al. 2017

Cell

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821

746

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Summary Elevated risk of developing Alzheimer’s disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth factor limitation or ER stress. Combined metabolomics and RNA-seq linked this anomalous autophagy to defective mTOR signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-β pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism.

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Section: Resultsmentioning

confidence: 99%

“…Network analysis was performed as previously described utilizing Shiny GAM (https://artyomovlab.wustl.edu/shiny/gam/) (Sergushichev et al, 2016; Vincent et al, 2015). We considered a network of chemical mappings between carbon atoms in substrates and products for all annotated reactions in KEGG database using RPAIRs entries.…”

Section: Methods Detailsmentioning

confidence: 99%

TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease

Ulland

Song

Huang

et al. 2017

Cell

Self Cite

821

746

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“…To understand the variation in metabolic gene expression networks between macrophage populations we have reviewed and analyzed Immgen data profiling macrophages in various tissues [31] using network analysis approaches developed in our group [5, 32, 33]. First, we have compared metabolic networks in the non-activated bone-marrow macrophages against non-activated peritoneal macrophages combining all the types of peritoneal macrophages available in Immgen.…”

Section: Metabolic Gene Expression and Macrophage Originmentioning

confidence: 99%

Integrating immunometabolism and macrophage diversity

Artyomov

Sergushichev

Schilling

2016

Seminars in Immunology

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153

126

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Macrophages are heterogeneous cells that play a key role in inflammatory and tissue reparative responses. Over the past decade it has become clear that shifts in cellular metabolism are important determinants of macrophage function and phenotype. At the same time, our appreciation of macrophage diversity in vivo has also been increasing. Factors such as cell origin and tissue localization are now recognized as important variables that influence macrophage biology. Whether different macrophage populations also have unique metabolic phenotypes has not been extensively explored. In this article, we will discuss the importance of understanding how macrophage origin can modulate metabolic programming and influence inflammatory responses.

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“…The metabolic network was analyzed using the network tool Shiny GAM: integrated analysis of genes and metabolites (https://artyomovlab.wustl.edu/shiny/gam/) (32) to identify interactions between metabolites and DEGs generated by spaceflight and simulated microgravity. The criteria were limited by a fold change >2 and a value of P < 0.05.…”

Section: Methodsmentioning

confidence: 99%

Spaceflight/microgravity inhibits the proliferation of hematopoietic stem cells by decreasing Kit‐Ras/cAMP‐CREB pathway networks as evidenced by RNA‐Seq assays

et al. 2019

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Exposure to spaceflight and microgravity causes physiologic and psychologic changes including bone loss, cardiovascular dysfunction, and immune dysfunction. Anemia and hematopoietic disorders are observed in astronauts after spaceflight. Hematopoietic stem and progenitor cells (HSPCs), which can self‐renew and give rise to all blood cells, play vital roles in hematopoiesis and homeostasis; however, the molecular mechanisms responsible for the impacts of microgravity on the proliferation of HSPCs remain unclear. We maintained mouse bone marrow HSPCs in the presence of stem cell factor for 12 d under spaceflight and simulated microgravity conditions, respectively, and analyzed cell proliferation and gene expression. Both spaceflight and simulated microgravity significantly decreased the number of HSPCs, mainly by blocking cell cycle at G1/S transition, but did not affect their differentiation abilities. RNA‐sequencing data indicated that genes related to cell proliferation were down‐regulated, whereas the genes related to cell death were up‐regulated under microgravity. Among the gene signatures, we identified that the Kit‐Ras/cAMP–cAMP response element‐binding protein pathway might be one of the major microgravity‐regulated pathways during HSPC proliferation. Furthermore, the quantification of notable genes was validated at the mRNA levels under simulated microgravity condition. Overall, these results would help us to understand the intracellular molecular mechanisms regulating microgravity‐inhibited proliferation of HSPCs.—Wang, P., Tian, H., Zhang, J., Qian, J., Li, L., Shi, L., Zhao, Y. Spaceflight/microgravity inhibits the proliferation of hematopoietic stem cells by decreasing Kit‐Ras/cAMP‐CREB pathway networks as evidenced by RNA‐Seq assays. FASEB J. 33, 5903–5913 (2019). http://www.fasebj.org

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GAM: a web-service for integrated transcriptional and metabolic network analysis

Cited by 87 publications

References 31 publications

TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease

TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease

Integrating immunometabolism and macrophage diversity

Spaceflight/microgravity inhibits the proliferation of hematopoietic stem cells by decreasing Kit‐Ras/cAMP‐CREB pathway networks as evidenced by RNA‐Seq assays

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