Dataset Information

Metabolic programming of macrophage functions and pathogens control.

ABSTRACT: Macrophages (M?) are central players in mediating proinflammatory and immunomodulatory functions. Unchecked M? activities contribute to pathology across many diseases, including those caused by infectious pathogens and metabolic disorders. A fine balance of M? responses is crucial, which may be achieved by enforcing appropriate bioenergetics pathways. Metabolism serves as the provider of energy, substrates, and byproducts that support differential M? characteristics. The metabolic properties that control the polarization and response of M? remain to be fully uncovered for use in managing infectious diseases. Here, we review the various metabolic states in M? and how they influence the cell function.

SUBMITTER: Koo SJ

PROVIDER: S-EPMC6488820 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Metabolic programming of macrophage functions and pathogens control.

Koo Sue-Jie SJ Garg Nisha J NJ

Redox biology 20190420

Macrophages (Mφ) are central players in mediating proinflammatory and immunomodulatory functions. Unchecked Mφ activities contribute to pathology across many diseases, including those caused by infectious pathogens and metabolic disorders. A fine balance of Mφ responses is crucial, which may be achieved by enforcing appropriate bioenergetics pathways. Metabolism serves as the provider of energy, substrates, and byproducts that support differential Mφ characteristics. The metabolic properties tha ...[more]

PMID: 31048245

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Project description:BackgroundThe reconstruction of context-specific metabolic models from easily and reliably measurable features such as transcriptomics data will be increasingly important in research and medicine. Current reconstruction methods suffer from high computational effort and arbitrary threshold setting. Moreover, understanding the underlying epigenetic regulation might allow the identification of putative intervention points within metabolic networks. Genes under high regulatory load from multiple enhancers or super-enhancers are known key genes for disease and cell identity. However, their role in regulation of metabolism and their placement within the metabolic networks has not been studied.MethodsHere we present FASTCORMICS, a fast and robust workflow for the creation of high-quality metabolic models from transcriptomics data. FASTCORMICS is devoid of arbitrary parameter settings and due to its low computational demand allows cross-validation assays. Applying FASTCORMICS, we have generated models for 63 primary human cell types from microarray data, revealing significant differences in their metabolic networks.ResultsTo understand the cell type-specific regulation of the alternative metabolic pathways we built multiple models during differentiation of primary human monocytes to macrophages and performed ChIP-Seq experiments for histone H3 K27 acetylation (H3K27ac) to map the active enhancers in macrophages. Focusing on the metabolic genes under high regulatory load from multiple enhancers or super-enhancers, we found these genes to show the most cell type-restricted and abundant expression profiles within their respective pathways. Importantly, the high regulatory load genes are associated to reactions enriched for transport reactions and other pathway entry points, suggesting that they are critical regulatory control points for cell type-specific metabolism.ConclusionsBy integrating metabolic modelling and epigenomic analysis we have identified high regulatory load as a common feature of metabolic genes at pathway entry points such as transporters within the macrophage metabolic network. Analysis of these control points through further integration of metabolic and gene regulatory networks in various contexts could be beneficial in multiple fields from identification of disease intervention strategies to cellular reprogramming.

Dataset Information

Metabolic programming of macrophage functions and pathogens control.

Publications

Metabolic programming of macrophage functions and pathogens control.

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