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2015 ; 16
(ä): 809
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Integrated metabolic modelling reveals cell-type specific epigenetic control
points of the macrophage metabolic network
#MMPMID26480823
Pacheco MP
; John E
; Kaoma T
; Heinäniemi M
; Nicot N
; Vallar L
; Bueb JL
; Sinkkonen L
; Sauter T
BMC Genomics
2015[Oct]; 16
(ä): 809
PMID26480823
show ga
BACKGROUND: The 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. METHODS:
Here 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. RESULTS: To 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.
CONCLUSIONS: By 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.