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Integration of Biological Networks for Acidithiobacillus thiooxidans Describes a Modular Gene Regulatory Organization of Bioleaching Pathways

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Integration of Biological Networks for Acidithiobacillus thiooxidans Describes a Modular Gene Regulatory Organization of Bioleaching Pathways

María Paz Cortés et al. Front Mol Biosci.

Abstract

Acidithiobacillus thiooxidans is one of the most studied biomining species, highlighting its ability to oxidize reduced inorganic sulfur compounds, coupled with its elevated capacity to live under an elevated concentration of heavy metals. In this work, using an in silico semi-automatic genome scale approach, two biological networks for A. thiooxidans Licanantay were generated: (i) An affinity transcriptional regulatory network composed of 42 regulatory family genes and 1,501 operons (57% genome coverage) linked through 2,646 putative DNA binding sites (arcs), (ii) A metabolic network reconstruction made of 523 genes and 1,203 reactions (22 pathways related to biomining processes). Through the identification of confident connections between both networks (V-shapes), it was possible to identify a sub-network of transcriptional factor (34 regulators) regulating genes (61 operons) encoding for proteins involved in biomining-related pathways. Network analysis suggested that transcriptional regulation of biomining genes is organized into different modules. The topological parameters showed a high hierarchical organization by levels inside this network (14 layers), highlighting transcription factors CysB, LysR, and IHF as complex modules with high degree and number of controlled pathways. In addition, it was possible to identify transcription factor modules named primary regulators (not controlled by other regulators in the sub-network). Inside this group, CysB was the main module involved in gene regulation of several bioleaching processes. In particular, metabolic processes related to energy metabolism (such as sulfur metabolism) showed a complex integrated regulation, where different primary regulators controlled several genes. In contrast, pathways involved in iron homeostasis and oxidative stress damage are mainly regulated by unique primary regulators, conferring Licanantay an efficient, and specific metal resistance response. This work shows new evidence in terms of transcriptional regulation at a systems level and broadens the study of bioleaching in A. thiooxidans species.

Keywords: Acidithiobacillus thiooxidans; bioleaching; biological networks; biotechnology; co-regulation.

Figures

Figure 1
Figure 1
Acidithiobacillus thiooxidans Licanantay affinity transcriptional regulatory network. The figure shows the interconnectivity (black arrows) between transcriptional factor nodes. Rectangular nodes (dark gray) correspond to transcriptional factors not regulated by others (origons). Oval nodes (light gray) represent transcriptional factors member of chain regulatory cascades. The number in parenthesis next to each transcriptional factor name is the number of operon targets for that transcriptional factor in the affinity network.
Figure 2
Figure 2
Selected metabolic pathways related to bioleaching in the context of A. thiooxidans Licanantay metabolic network (sub-categories). Six metabolic processes were selected for this study: RISC oxidation (orange); Sulfur assimilation (violet); Energy generation (red); heme biosynthesis (green); spermidine biosynthesis (cyan); and NAD biosynthesis (blue). Genes associated to each of these pathways are listed next to the corresponding reactions.
Figure 3
Figure 3
Acidithiobacillus thiooxidans Licanantay bioleaching co-regulatory network. Transcriptional factors in the co-regulatory network are depicted as rectangular (dark gray) and oval nodes (light gray). Rectangular nodes correspond to primary regulators while oval nodes are transcriptional factors member of chain regulatory cascades. Leaf nodes are target operons colored according to their metabolic bioleaching sub-categories. Solid arcs represent regulation between transcriptional factors and dotted arcs represent regulation of metabolic operons. Hierarchical levels are listed at the bottom of the figure. Red circle highlights CysB transcription factor. Colored arcs (red, green, and light blue) correspond to connections forming directed cycles in the network. There are three directed cycles: a small one between FLIA and IHF (green arcs) and two larger ones that share the path made by light-blue arcs. Thus, removing any green and light blue pair of arcs breaks all directed cycles (minimum feedback arc sets).

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