Integrative Multiomics and Regulatory Network Analyses Uncovers the Role of OAS3, TRAFD1, miR-222-3p, and miR-125b-5p in Hepatitis E Virus Infection

Figures

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  Figure 1. Annotation heatmap displays the distribution (expression) of the top 10 down and upregulated DEGs in the case of Mo (left panel) and WB (right panel). The cluster dendrograms signifying the Euclidean distance-based hierarchical clustering for both rows and columns are shown along the left and top sides of the plot. Sample type annotation bar is shown at the top of the heatmap. DEGs, Differentially Expressed Genes; Mo, Monocytes; WB, Whole Blood.

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  Figure 2. (A) Hierarchical clustering dendrogram of 2016 WB-DEGs clustered based on dissTOM together with original (16) and merged (9) module colors. The sizes of the original modules were as follows: black (108), blue (300), brown (207), cyan (42), green (151), green-yellow (63), grey (6), magenta (85), midnight-blue (39), pink (94), purple (65), red (126), salmon (43), tan (51), turquoise (455), yellow (181). In addition, the sizes of merged modules were as follows: black (392), blue (739), cyan (127), green-yellow (63), grey (6), purple (65), red (126), salmon (43), turquoise (455). (B) 3D MDS plot where each colored point denotes a gene belonging to the module of its equivalent color in the case of the WB group. (C) Representation of WGCN as a TOM plot for WB-DEGs. Genes within columns and their corresponding rows were hierarchically clustered by cluster dendrograms (displayed along the top and left side of the plot). Progressively darker and lighter red colors within the matrix indicate higher and lower topological overlap among genes. Dark-colored blocks along the diagonal signify the modules. (D) Expression heatmap of turquoise module genes where the rows and columns correspond to…

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  Figure 3. (A) Hierarchical clustering dendrogram of 93 Mo-DEGs clustered based on dissTOM and two color-coded modules obtained using Dynamic Tree Cut. The sizes of the module were as follows: blue (42) and turquoise (51). (B) 3D MDS plot where each colored point denotes a gene belonging to the module of its equivalent color in the case of the Mo group. (C) Representation of WGCN as a TOM plot for Mo-DEGs. Genes within columns and their corresponding rows were hierarchically clustered by cluster dendrograms (displayed along the top and left side of the plot). Progressively darker and lighter red colors within the matrix indicate higher and lower topological overlap among genes. Dark-colored blocks along the diagonal signify the modules. (D) Expression heatmap of turquoise module genes where the rows and columns correspond to genes and samples. The red and green color bands within the heatmap imply higher and lower expression levels across turquoise module genes. In addition, the corresponding ME expression levels (along the y-axis) across all samples (along the x-axis) are displayed at the bottom panel of the module heatmap in the form of a barplot.

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  Figure 4. (A) PPI network comprising 114 nodes and 545 interaction edges constructed using the STRING database corresponding to interaction score >0.9. The red- and blue-colored nodes signify up and downregulated proteins. (B) Top scoring PPI module comprises 28 nodes and 374 edges. PPI, Protein-Protein Interaction.

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  Figure 5. (A) HEV-specific three-node miRNA FFL comprising 16 nodes and 51 edges. (B) Highest-order subnetwork motif comprising one TF (TRAFD1), one miRNA (miR-222-3p), and one mRNA (OAS3). Red-colored octagonal nodes signify hub mRNAs, green-colored diamond nodes signify TFs, and magenta-colored circular nodes signify miRNAs. HEV, Hepatitis E Virus; FFL, Feed-Forward Loop; TF, Transcription Factor; TRAFD1, TRAF-Type Zinc Finger Domain Containing 1; OAS3, 2′-5′-Oligoadenylate Synthase 3.

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  Figure 6. Docked mode of OAS3_D3-TRAFD1 complex and its structural mapping of intramolecular interfaces. (A) Cartoon representation of OAS3_D3-TRAFD1 docked complex having low energy score determined by HADDOCK docking. OAS3_D3 is displayed in blue color, and TRAFD1 is represented in magenta color. (B) A surface representation of OAS3_D3-TRAFD1 complex. (C) Interacting residues between OAS3_D3 and TRAFD1 obtained through hydrogen bonding between the side chain of OAS3_D3 and the main chain of TRAFD1 are shown in licorice representation, OAS3_D3 residues (blue) and TRAFD1 residues (in magenta). (D) Interacting residues between OAS3_D3 and TRAFD1 obtained through hydrogen bonding between the side chain of OAS3_D3 and the side chain of TRAFD1 are shown in licorice representation, OAS3_D3 residues (blue) and TRAFD1 residues (in magenta). The atomic distances are shown in yellow dotted lines in angstrom (Å).