438741 Integrated Metabolic Modelling Reveals Cell-Type Specific Epigenetic Control Points of the Macrophage Metabolic Network

Thursday, September 17, 2015: 3:30 PM
Crowne Plaza Heidelberg City Centre
Maria Pires Pacheco1, Elisabeth John2, Tony Kaoma3, Merja Heinäniemi4, Nathalie Nicot3, Laurent Vallar3, Jean-Luc Bueb1, Lasse Sinkkonen1,2 and Thomas Sauter1, (1)Life Sciences Research Unit, University of Luxembourg, L-1511 Luxembourg, Luxembourg, (2)Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Esch-sur-Alzette, Luxembourg, (3)Genomics Research Unit, CRP-Santé, L-1526 Luxembourg, Luxembourg, (4)) Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland

Fast reconstruction of cell type-specific metabolic models and understanding the epigenetic regulatory mechanisms underlying the observed differences will be increasingly important at the age of personalized medicine. To enable fast creation of high-quality metabolic models from gene expression data, we have developed a new workflow named FASTCORMICS (Pires Pacheco, John et al., under revision). By using the BARCODE to determine active and inactive reactions, we avoid an arbitrary values for presence calls but base our selection on a strong data foundation. Moreover, has a low computational demand and outperforms its competitors in speed (for details on the workflow see the abstract of Martins Conde et al.). Applying FASTCORMICS, we have generated metabolic models for 63 primary human cell types based on microarray data, thus revealing significant differences between metabolic networks of the different cell types. To better understand the cell type-specific regulation of the alternative metabolic pathways we built multiple microarray-based metabolic models at different time points of differentiation of primary human monocytes to macrophages and performed ChIP-Seq experiments in macrophages for histone H3 lysine 27 acetylation (H3K27ac) in order to map the active enhancers. We focused on metabolic genes under high regulatory load from multiple strong enhancers that are known to be key genes for disease and cell identity but whose role in the regulation of metabolism and their placement within the metabolic networks has not been studied. We identified these genes to show the most cell type-restricted and abundant expression profiles within their respective metabolic pathways. Importantly, the high regulatory load genes are associated to reactions significantly enriched for transport reactions and other pathway entry points, suggesting that they are the critical regulatory control points for cell type-specific metabolism. Finally, we provide examples of selected macrophage-specific pathways and their regulators.


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