Abstract
Metaboloepigenetics is a newly coined term in biological sciences that investigates the crosstalk between epigenetic modifications and metabolism. The reciprocal relation between biochemical transformations and gene expression regulation has been experimentally demonstrated in cancers and metabolic syndromes. In this study, we explored the metabolism-histone modifications crosstalk by topological analysis and constraint-based modeling approaches in the budding yeast. We constructed nine models through the integration of gene expression data of four mutated histone tails into a genome-scale metabolic model of yeast. Accordingly, we defined the centrality indices of the lowly expressed enzymes in the undirected enzyme-centric network of yeast by CytoHubba plug-in in Cytoscape. To determine the global effects of histone modifications on the yeast metabolism, the growth rate and the range of possible flux values of reactions, we used constraint-based modeling approach. Centrality analysis shows that the lowly expressed enzymes could affect and control the yeast metabolic network. Besides, constraint-based modeling results are in a good agreement with the experimental findings, confirming that the mutations in histone tails lead to non-lethal alterations in the yeast, but have diverse effects on the growth rate and reveal the functional redundancy.
Highlights
Biological systems contain many highly interconnected processes that function in a coordinated fashion to produce cellular behavior
Recent studies propose that the impairments in the interface between epigenetics and metabolism are strongly associated with development of cancers [7] and metabolic syndromes [8]
The cellular metabolism and the epigenetic modifications are not independent entities, and they would better be viewed as an integrated discipline, metaboloepigenetics that focuses on the crosstalk between them [9]
Summary
Biological systems contain many highly interconnected processes that function in a coordinated fashion to produce cellular behavior. Epigenetic mechanisms, as a constituent of gene expression regulation machinery, alter transcriptional activities of various genes, independently of changes in their nucleotides sequences [2]. These mechanisms include modifications of DNA and histone proteins, such as different combinations of histone acetylation, methylation and phosphorylation which shape, the socalled ‘histone code’ and DNA methylation. Advantages and disadvantages of different approaches of integration of expression data into constraint-based modeling have been evaluated [23]. The first budding yeast GSMM, iFF708, [25] was released in 2003 This model consists of 708 genes and 1175 reactions. The improved versions of yeast GSMM were reconstructed; iND750 [26], iLL672 [27], iLN800 [28], iMM904 [29], improved iMM904 [30], and yeast 5 [31] released in the standard format using jamboree approach [32] which is the most up to date version
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