Figure 1.
Schematic diagram of the construction and analysis of the integrative regulatory network.
ChIP-seq data were used to determine target genes and miRNAs of transcription factors. miRNA target genes were predicted using PicTar or TargetScan algorithms together with conservation information. The three types of regulations form the basic network. The sign of each regulatory interaction was determined based on the correlation between TF binding and gene expression, Extra edges of protein-protein or TF-TF combinatorial interactions were incorporated. We studied the topological structure of the integrated network, including hierarchical organization and motif enrichment.
Figure 2.
Topology of the integrated regulatory network in C. elegans.
The network contains 393 TFs (red circles), 160 miRNAs (cyan circles) and 5574 non-TF protein-coding genes (green circles). For 22 of these TFs, we determined the target genes and miRNAs. Topological features of the three node types were shown in the lower table.
Figure 3.
Distributions of the topological features of each node type in C. elegans integrated regulatory network.
(A) The number of regulatory TFs for miRNAs; (B) the number of regulatory TFs for protein-coding genes; (C) the number of regulatory miRNAs for protein-coding genes; (D) the number of target genes of miRNAs. Each is best fitted to an exponential distribution as shown by the corresponding inset.
Figure 4.
Hierarchical illustration of the integrated regulatory network.
(A) The C. elegans integrated gene regulatory network exhibits a 7-layer structure with 3 layers of TFs (red circles) and 4 layers of miRNAs (cyan circles). TF-TF and TF-miRNA regulatory interactions were shown as dark and light arrows respectively. Essential transcription factors are labeled by a blue circle. (B) TFs in the three layers show significant difference in their average number of regulatory miRNAs (left), average degree in protein-protein interaction network (middle) and tissue specificity (right).
Figure 5.
Correlation of gene expression with TF binding signals in DNA regions around transcription start site (−2 kb∼2 kb).
Based on their correlation patterns, TFs were divided into positive (red) and negative (blue) regulators.
Figure 6.
Representative network motifs in integrated gene regulatory network for C. elegans.
(A) motifs in the unsigned network. (B) motifs in the signed network. (C) a composite motif in which a miRNA represses two physically interacting genes. P-values are calculated by comparing the number of occurrences of each motif in the real network with those in random networks.
Figure 7.
Intra-regulation among miRNA/host-gene pairs in C. elegans.
The regulatory relationships among the 39 miRNA/host-gene pairs (the miRNAs are embedded within the intron of the host in the same sense orientation) form a small miRNA-host network consisting of 5 interactions. The auto-regulated mir-233/w03g11.4 was highlighted in yellow color, for which mir-233 is predicted to repress the expression of its host-gene, w03g11.4.
Figure 8.
Integrated regulatory networks in human and mouse.
(A) Basic statistics. (B) Hierarchical organization of TFs in human and mouse. (C) the miRNA-host network in human. There are 1,426 interactions with 8 auto-regulated miRNA/host-gene pairs (yellow).
Figure 9.
Representative network motifs in the integrated regulatory network for human and mouse.
(A) Significant motifs in the regulatory networks. (B) A significant motif enriched in the networks with further incorporation of TF-TF physical interactions. The significances of each motif in human and mouse were shown.