Integrated network analysis reveals distinct regulatory roles of transcription factors and micrornas Yu Guo 1,2,4, Katherine Alexander 1, Andrew G Clark 1, Andrew Grimson 1 and Haiyuan Yu 2,3* 1 Department of Molecular Biology and Genetics, 2 Weill Institute for Cell and Molecular Biology, 3 Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14853, USA. 4 Present address: Computational and Systems Biology, Genome Institute of Singapore, 60 Biopolis Street, #02-01 Genome, Singapore 138762, Singapore *To whom correspondence should be addressed. Email: haiyuan.yu@cornell.edu
SUPPLEMENTARY FIGURE LEGENDS Supplementary Figure 1 Synergistic effect of TF and mirna regulation on the protein interactions of their targets. Average pairwise distance of protein products of gene targets regulated by multiple TFs (A) or mirnas (B) in the protein-protein interaction network. Difference in the average pairwise distances between the first and last bins is calculated by the t-test. Supplementary Figure 2 Analysis of the synergistic effects of mirnas on target genes using experimentally verified mirna targets. (A) LOD values for enrichment of mrna co-expression between gene pairs jointly regulated by multiple mirnas. (B) LOD values for enrichment of protein co-expression between gene pairs jointly regulated by multiple mirnas. (C) LOD values for enrichment of protein-protein interactions between gene pairs jointly regulated by mirnas (D) LOD values for the likelihood of gene pairs jointly regulated by multiple mirnas to be associated with the same disease. *P < 0.05. P-values are calculated by the Z-test. Difference between the first and last bins of each panel is calculated by the chi-squared test. Supplementary Figure 3 Co-regulation of gene targets by inter-regulating TFs and mirnas. (A) Percentage of mirnas that share targets with TFs that regulate them. (B) Percentage of TFs that share targets with mirnas that regulate them. Error bars indicate ±SE. Supplementary Figure 4 Inter-regulation of TFs and mirnas. Distribution of the fraction of co-expressed targets of (A) TF pairs regulated by the same mirna, (B) TF pairs regulated by the same TF, and (C) mirna pairs regulated by the same TF. Supplementary Figure 5 Inter-regulation of TFs and mirnas. Distribution of the fraction of interacting targets of (A) TF pairs regulated by the same mirna, (B) TF pairs regulated by the same TF, and (C) mirna pairs regulated by the same TF. Supplementary Figure 6 Inter-regulation of TFs and mirnas. Distribution of the similarity scores of (A) TF pairs regulated by the same mirna, (B) TF pairs regulated by the same TF, and (C) mirna pairs regulated by the same TF.
A B average pairwise distance 4.5 4.4 4.3 4.2 4.1 4 average pairwise distance of TF targets average pairwise distance of mirna targets P < 10 4.6-20 P < 10-20 >=0 >=1 >=2 >=3 >=4 >=5 number of common regulators average pairwise distance 4.4 4.2 4 3.8 3.6 3.4 >=0 >=1 >=2 >=3 >=4 >=5 number of common regulators Supplementary Figure 1
A Enrichment of mrna co-expression B Enrichment of protein co-expression 1.5 1.5 Log odds ratio 1 0.5 0 Log odds ratio 1 0.5 0-0.5 >=1 >=2 >=3 Number of common regulators -0.5 >=1 >=2 >=3 >=4 Number of common regulators C Log odds ratio P < 10-5 Enrichment of protein-protein interactions D Enrichment of target gene pairs causing the same disease 2 * 2 1.5 1.5 P = 0.0057 1 * 1 * 0.5 0.5 0 0-0.5-0.5 >=1 >=2 >=3 >=1 >=2 Number of common regulators Number of common regulators Log odds ratio Supplementary Figure 2
A B Percentage of TF-miRNA pairs that share targets 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% regulating TF P < 0.0001 P <0.0001 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Percentage of mirna-tf pairs that share targets regulating mirna Supplementary Figure 3
A B C TFs regulated by the same mirna TFs regulated by the same TF mirnas regulated by the same TF Fraction of targets that coexpress 0.1 0.2 0.3 0.4 0.5 0.6 0.1 0.2 0.3 0.4 0.5 0.6 P = 0.038 0.0 0.2 0.4 0.6 P = 0.010 shared mirna shared TF shared TF Supplementary Figure 4
A B C TFs regulated by the same mirna TFs regulated by the same TF mirnas regulated by the same TF Fraction of targets that phyiscally interact 0.00 0.05 0.10 0.15 0.00 0.05 0.10 0.15 P < 10-4 P = 0.001 0.00 0.05 0.10 0.15 0.20 shared mirna shared TF shared TF Supplementary Figure 5
A B C TFs regulated by the same mirna TFs regulated by the same TF mirnas regulated by the same TF Similarity Score 0.10 0.20 0.30 0.15 0.20 0.25 0.30 0.35 0.40 P < 10-12 P < 10-15 0.0 0.1 0.2 0.3 0.4 shared mirna shared TF shared TF Supplementary Figure 6