Quantitative Identification of Compound-Dependent On-Modules and Differential Allosteric Modules From Homologous Ischemic Networks

Abstract

Module-based methods have made much progress in deconstructing biological networks. However, it is a great challenge to quantitatively compare the topological structural variations of modules (allosteric modules [AMs]) under different situations. A total of 23, 42, and 15 coexpression modules were identified in baicalin (BA), jasminoidin (JA), and ursodeoxycholic acid (UA) in a global anti-ischemic mice network, respectively. Then, we integrated the methods of module-based consensus ratio (MCR) and modified Z_summary module statistic to validate 12 BA, 22 JA, and 8 UA on-modules based on comparing with vehicle. The MCRs for pairwise comparisons were 1.55% (BA vs. JA), 1.45% (BA vs. UA), and 1.27% (JA vs. UA), respectively. Five conserved allosteric modules (CAMs) and 17 unique allosteric modules (UAMs) were identified among these groups. In conclusion, module-centric analysis may provide us a unique approach to understand multiple pharmacological mechanisms associated with differential phenotypes in the era of modular pharmacology.

Figure 1

Hierarchic cluster tree and modules of the three drug groups. (a–c) The hierarchic cluster tree (dendrogram) of baicalin (BA), jasminoidin (JA), and ursodeoxycholic acid (UA), each major tree branch represents a module, and each module is labeled with a color below the dendrogram. (d) The number and size of the modules in the three groups are shown. The red, green, and blue bars represent the number of modules in the BA, JA, and UA groups, respectively. The red dot, green square, and blue triangle indicate the mean size of the modules in the BA, JA, and UA groups, respectively. The vertical line indicates the range of module size in each group.

Figure 2

Concordance of modules among the three groups. (a) Concordance of modules between the baicalin (BA) and jasminoidin (JA) groups; each row of the table corresponds to the BA modules (labeled by color name and module size), and each column corresponds to the JA modules. Numbers in the table indicate gene counts in the intersection of the corresponding modules of the BA and JA groups. Coloring of the table encodes ‐log (P), with P being the Fisher's exact test P value for the overlap of the two modules. Any P value < 0.05 is considered significant. The darker the red color, the more significant the correlation. (b) The number of modules with a certain amount of overlapping genes between the BA and JA groups is shown. (c) Concordance of modules between the BA and ursodeoxycholic acid (UA) groups; the table legend is the same as panel a. (d) The number of modules with a certain amount of overlapping genes between the BA and UA groups. (e) Concordance of modules between the JA and UA groups; the table legend is the same as a. (f) The number of modules with a certain amount of overlapping genes between the JA and UA groups. (g) The module‐based consensus ratios (MCRs) among the three drug groups.

Figure 3

The conserved allosteric modules (CAMs) and their significant biological functions are shown. Modules in the orange dotted box are identified from the baicalin (BA) group, modules in the light blue dotted box are identified from the jasminoidin (JA) group, and modules in the light green dotted box are identified from the ursodeoxycholic acid (UA) group. The top five significantly enriched functions (black font color represents Gene Ontology (GO) terms and the red font color represents KEGG pathways) of each module are listed. The Venn diagram in the middle indicates to which conserved module belongs to which groups. MAPK, mitogen‐activated protein kinase; NA, not applicable; VE, vehicle group.

Figure 4

Classification of significant biological functions for the three drug groups are shown. (a–f) The classification of significantly enriched Gene Ontology (GO) terms and pathways (P < 0.05) for the baicalin (BA) (a & b), the jasminoidin (JA) (c and d), and the ursodeoxycholic acid (UA) (e and f) groups. (g) The overlapped circles show the significantly enriched GO terms for the three groups. (h) The overlapped circles show the significantly enriched KEGG pathways for the three groups.

Figure 5

The unique allosteric modules (UAMs) and their significant biological functions. Modules in the orange dotted box are identified from the baicalin (BA) group, the modules in the light blue dotted box are identified from the jasminoidin (JA) group, and the modules in the light green dotted box are identified from the ursodeoxycholic acid (UA) group. The top five significantly enriched functions (black font color represents the Gene Ontology (GO) terms and the red font color represents the KEGG pathways) of each module are listed. These common and divergent biological functions of each group are classified and visualized in the middle of this figure (the black font color represents GO terms' classification and the red font color represents KEGG pathways' classification; the number of terms in a certain category are also listed). NA, not applicable.

Figure 6

(a) Schematic diagram of the contributing pathways of the three drug groups. The top five enriched pathways of the unique allosteric modules (UAMs) are listed. The orange color lines represent pathways enriched by the UAMs in the baicalin (BA) group, and the light blue lines represent the UAMs in the jasminoidin (JA) group; no pathway is enriched by the UAMs in the ursodeoxycholic acid (UA) group. The length of these lines indicates its approximate enriched ‐log(P value). (b) Western blotting analysis indicates the active patterns of mitogen‐activated protein kinase 6 (MAP2K6) under different conditions. *P < 0.05 vs. vehicle. MAPK, mitogen‐activated protein kinase.