Research design: L.J. and L.L. Analysis: Y.W., M.L., X.G., B.Z., H.L., Y.L. and J.H. Contribution to the composition of the manuscript: Y.W., M.L., L.J. and L.L. All authors have read and agreed to the published version of the manuscript.

Figure 1. Clean reads acquired and PCA analysis. (A) Clean reads of HERVs and genes mapped on the reference genome, including four datasets with two duplicates: IFN-β-treated THP1 cells (IFN-β_N), IFN-β-treated THP1_IFNAR1_KO cells (IFN-β_KO1), IFN-β-treated THP1_IFNAR2_mutant cells (IFN-β_MT2), and the untreated THP1 cells (N). PCA analysis of the transformed expression values of HERV loci (B) and human genes (C).

Figure 1. Clean reads acquired and PCA analysis. (A) Clean reads of HERVs and genes mapped on the reference genome, including four datasets with two duplicates: IFN-β-treated THP1 cells (IFN-β_N), IFN-β-treated THP1_IFNAR1_KO cells (IFN-β_KO1), IFN-β-treated THP1_IFNAR2_mutant cells (IFN-β_MT2), and the untreated THP1 cells (N). PCA analysis of the transformed expression values of HERV loci (B) and human genes (C).

Figure 2. Screening and classification of DEHERVs. (A–C) Volcano plots of the three groups (KO1, KO2, and N). Red and blue-colored dots represent upregulated and downregulated HERV loci, respectively (adjusted P-value < 0.05 and |log2 fold change| > 1). Gray-colored dots represent loci with no significant differential expression. (D–F) Pie charts showing the number of DEHERVs in each superfamily of three groups. (G–I) Distribution of DEHERV loci on the plus (green point) and minus (orange point) strands of each chromosome. The blue bar represents the length of each human chromosome.

Figure 2. Screening and classification of DEHERVs. (A–C) Volcano plots of the three groups (KO1, KO2, and N). Red and blue-colored dots represent upregulated and downregulated HERV loci, respectively (adjusted P-value < 0.05 and |log2 fold change| > 1). Gray-colored dots represent loci with no significant differential expression. (D–F) Pie charts showing the number of DEHERVs in each superfamily of three groups. (G–I) Distribution of DEHERV loci on the plus (green point) and minus (orange point) strands of each chromosome. The blue bar represents the length of each human chromosome.

Figure 3. Screening and classification of differentially expressed genes (DEGs). (A–C) Volcano plots of the three groups (KO1, KO2, and N). Red- and blue-colored dots represent upregulated and downregulated genes, respectively (adjusted P-value < 0.05 and |log2 fold change| > 1). Gray-colored dots represent loci with no significant differential expression. (D–F) Circos plots showing DEGs (red column) and DEHERVs (green column) across chromosomal locations. The length of the column represents the absolute value of the log2 fold change.

Figure 3. Screening and classification of differentially expressed genes (DEGs). (A–C) Volcano plots of the three groups (KO1, KO2, and N). Red- and blue-colored dots represent upregulated and downregulated genes, respectively (adjusted P-value < 0.05 and |log2 fold change| > 1). Gray-colored dots represent loci with no significant differential expression. (D–F) Circos plots showing DEGs (red column) and DEHERVs (green column) across chromosomal locations. The length of the column represents the absolute value of the log2 fold change.

Figure 4. Identification of DEHERV-G pairs in each dataset. (A) Number and proportion of DEHERV-G pairs in the three groups. The dark blue column located on the left side of each group indicates the number of DEHERV-G pairs, and the column located on the right side of each group represents the proportion of four patterns: upregulated DEHERV and DEGs (green), downregulated DEHERV and DEGs (yellow), upregulated DEHERV and downregulated DEGs (red), and downregulated DEHERV and upregulated DEGs (light blue). (B) A Venn diagram of the DEHERV-G pair overlap across the three groups. Pink represents the KO1 group, green represents the KO2 group, and purple represents the N group. (C) Distribution of the components of the common DEHERV-G pairs on chromosomes. The green rectangle represents a DEHERV site, and the yellow triangle represents a DEG. (D) Heatmap of the different groups. Red indicates significantly increased gene expression, and blue indicates significantly decreased gene expression, with the intensity of color change from blue to red corresponding to a normalized log2 fold change from values −1 to 1.

Figure 4. Identification of DEHERV-G pairs in each dataset. (A) Number and proportion of DEHERV-G pairs in the three groups. The dark blue column located on the left side of each group indicates the number of DEHERV-G pairs, and the column located on the right side of each group represents the proportion of four patterns: upregulated DEHERV and DEGs (green), downregulated DEHERV and DEGs (yellow), upregulated DEHERV and downregulated DEGs (red), and downregulated DEHERV and upregulated DEGs (light blue). (B) A Venn diagram of the DEHERV-G pair overlap across the three groups. Pink represents the KO1 group, green represents the KO2 group, and purple represents the N group. (C) Distribution of the components of the common DEHERV-G pairs on chromosomes. The green rectangle represents a DEHERV site, and the yellow triangle represents a DEG. (D) Heatmap of the different groups. Red indicates significantly increased gene expression, and blue indicates significantly decreased gene expression, with the intensity of color change from blue to red corresponding to a normalized log2 fold change from values −1 to 1.

Figure 5. Functional enrichment analysis of DEHERV-G pair genes and PPI networks. GO analysis (A) and KEGG analysis (B) of DEGs with the top five biological processes (BPs), cell components (CC), and molecular function (MF) with the lowest p value (p < 0.05) of GO analysis included. The color of columns or bubbles represents the p value, and the length of the column or the size of the bubbles represents the number of counts. (C) PPI core networks of human genes. Circles represent protein-coding genes, and the darker the circle, the more genes are associated.

Figure 5. Functional enrichment analysis of DEHERV-G pair genes and PPI networks. GO analysis (A) and KEGG analysis (B) of DEGs with the top five biological processes (BPs), cell components (CC), and molecular function (MF) with the lowest p value (p < 0.05) of GO analysis included. The color of columns or bubbles represents the p value, and the length of the column or the size of the bubbles represents the number of counts. (C) PPI core networks of human genes. Circles represent protein-coding genes, and the darker the circle, the more genes are associated.