Integrated modeling framework reveals co-regulation of transcription factors, miRNAs and lncRNAs on cardiac developmental dynamics

Figures

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  Fig. 1. Overview of the web-based framework CGRM. CGRM establishes the cooperative regulation of TFs, lncRNAs and miRNAs on cardiac developmental dynamics. The main components of CGRM include computational modeling, interaction and association, and data resources

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  Fig. 2. Transcriptional gene regulation of hPSC-CM differentiation and maturation. A and B Comparison of the differentially expressed gene targets of cardiac TFs which were predicted by using three datasets of hESC/hiPSC-CMs and the significantly associated functions at the early stage (A) and late stage (B). C and D Cardiac TF-gene regulatory networks at the early (C) and late stages (D). Oval nodes represent the target genes of TF logics and are involved in heart development and function (in light red), contraction (in orange), ion transport and handling (in yellow) and stem cell pluripotency regulators (in light blue). Oval nodes with red and green borders indicate up- and down-regulated genes, respectively. The arrow edges indicate regulatory relationships of TF logics and target genes, and the thick edges indicate that the regulatory relations between TFs and target genes are conserved in both hESC-CMs and hiPSC-CMs

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  Fig. 3. Target genes co-regulated by cardiac TFs, miRNAs and lncRNAs during hPSC-CM differentiation and maturation. A and B The percentage of the conserved targets of miRNA-TF or lncRNA-TF among all heart targets of hESC-CMs at the early (A) and late (B) stages. The “conserved targets” refer to those that are commonly regulated by at least one (n ≥ 1) or two (n ≥ 2) shared miRNAs or lncRNAs in both hESC-CMs and hiPSC-CMs. C and D The cardiac gene regulatory networks (GRNs) of TF-miRNA-lncRNA at the early (C) and late (D) stages. Oval nodes represent the target genes of TFs and miRNAs or lncRNAs, and are involved in heart development and function (in light red), contraction (in orange), ion transport and handling (in yellow), apoptosis (in gray) and stem cell pluripotency regulators (in light blue). Oval nodes with red and green borders indicate up- and down-regulated genes, respectively. The arrow edges indicate regulatory relationships of TFs and miRNAs or lncRNAs on target genes, and the thick edges indicate conserved regulatory relations detected in both hESC-CMs and hiPSC-CMs

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  Fig. 4. Gene co-regulation of TFs, miRNAs and lncRNAs on the early and late stages of in vivo CM development. A Enrichment analysis of the co-regulated genes of TF-miRNA and TF-lncRNA related to heart development, function and disease during in vivo fetal embryo-derived atrial and ventricular CM development. The p values represent significance of the enrichment analysis based on hypergeometric distribution. B and C Comparison of the differentially expressed heart genes regulated by the cardiac TFs, miRNAs or lncRNAs. The datasets of hPSC-CMs and fetal embryo-derived atrial and ventricular CMs at the early stages (B) and late stages (C) were used. The number in the Venn diagram shows the number of heart targets shared by the different datasets. The numbers of “conserved heart targets” shown in the parentheses indicate how many target genes are regulated by at least one common TF, miRNA or lncRNA between hPSC-CMs and embryo-derived CMs, i.e., CM-AE, CM-AL, CM-VE and CM-VL. The associated pathways, processes and heart diseases with the conserved and specific target gene programs are shown correspondingly. The black bars correspond to conserved targets, and the open bars are those that are…

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  Fig. 5. Cardiac gene regulatory programs of TFs, miRNAs and lncRNAs in fetal embryo-developed atrial and ventricular CMs. A and B comparison of heart target genes generated from in vivo atrial and ventricular CMs with in vitro hPSC-CM data during the early (A) and late stages (B). The listed differentially expressed gene targets show the conserved regulatory programs between both in vivo and in vitro and the association with heart development and disease. Underlined TFs, miRNAs and lncRNAs indicate consistency of the target genes up- or down-regulated by these common factors between the in vivo atrial or ventricular CMs and hPSC-CMs. Among heart disease, HF = heart failure, arr = arrhythmia and cmp = cardiomyopathy. The boxes in red and green indicate up- and down-regulated target genes, respectively. C A proposed model of dynamic development of in vitro hPSC-CMs and in vivo embryo-CMs. Rectangle boxes show the associated biological processes and pathways of the target genes. Those in red indicate processes and pathways whose targets are up-regulated ↑, those in green are down-regulated ↓, and those in gray are both up- and down-regulated genes