Emergent Properties of the HNF4α-PPARγ Network May Drive Consequent Phenotypic Plasticity in NAFLD
Abstract
:1. Introduction
2. Materials and Methods
2.1. RAndom CIrcuit PErturbation (RACIPE) Analysis:
2.1.1. RACIPE Simulations
2.1.2. Z-Score Normalizations of The Steady State Values
2.1.3. Density Plots, Bimodality Coefficients, and Clustering Analysis:
2.2. Relative Stability Analysis
2.3. Dynamic Simulations
2.3.1. Bifurcation Diagrams
2.3.2. Switching of States
2.4. Randomization of Networks
2.5. Jensen–Shannon Divergence (JSD) and Plasticity Scores
2.6. Clinical Data Analysis
2.7. Statistical Tests and Correlation Coefficients
3. Results
3.1. Identification of a Core HNF4α-PPARγ Network in Hepatocytes
3.2. The Emergent Properties of This Core Regulatory Network Enable The Existence of Multiple Phenotypes
3.3. Multiple Stable States (Phenotypes) Can Co-Exist, Giving Rise To Phenotypic Plasticity
3.4. The Topology of the Core Regulatory Network is Designed to Enhance Phenotypic Plasticity
3.5. Clinical Data Support the Model Predictions
4. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Species | Production Rate (106 molecules hr−1) | Degradation Rate (hr−1) | References |
---|---|---|---|
HNF4A | 0.4540 | 0.0491 | [22] |
HNF1A | 0.0570 | 0.0494 | [23] |
PPARG | 0.0628 | 0.08 | [24] |
SREBF1 | 1.1058 | 0.1598 | [25] |
Description | Fold Change | Value | # of binding sites | Value | Threshold | Value | Reference (est: Estimated) |
---|---|---|---|---|---|---|---|
Self-Activation of HNF4A | 4 | 4 | 3 | est | |||
Self-Activation of HNF1A | 2 | 4 | 0.8 | est | |||
Self-Activation of PPARG | 9.514 | 5 | 6.320 | est | |||
Self-Activation of SREBF1 | 4 | 2 | 5.25 | est | |||
Activation of HNF4A by HNF1A | 4 | 3 | 0.8 | est | |||
Activation of HNF1A by HNF4A | 5.328 | 4 | 5.108 | est, [26] | |||
Activation of PPARG by SREBF1 | 3 | 2 | 5.25 | est, [27] | |||
Activation of SREBF1 by PPARG | 3.729 | 2 | 9.283 | est | |||
Inhibition of HNF4A by SREBF1 | 0.415 | 2 | 5 | [28] | |||
Inhibition of PPARG by HNF1A | 0.68 | 4 | 0.674 | [26] |
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Sahoo, S.; Singh, D.; Chakraborty, P.; Jolly, M.K. Emergent Properties of the HNF4α-PPARγ Network May Drive Consequent Phenotypic Plasticity in NAFLD. J. Clin. Med. 2020, 9, 870. https://doi.org/10.3390/jcm9030870
Sahoo S, Singh D, Chakraborty P, Jolly MK. Emergent Properties of the HNF4α-PPARγ Network May Drive Consequent Phenotypic Plasticity in NAFLD. Journal of Clinical Medicine. 2020; 9(3):870. https://doi.org/10.3390/jcm9030870
Chicago/Turabian StyleSahoo, Sarthak, Divyoj Singh, Priyanka Chakraborty, and Mohit Kumar Jolly. 2020. "Emergent Properties of the HNF4α-PPARγ Network May Drive Consequent Phenotypic Plasticity in NAFLD" Journal of Clinical Medicine 9, no. 3: 870. https://doi.org/10.3390/jcm9030870