Balancing plasticity and robustness in binary-fate cellular decision systems

Haldar, Kushal (2025) Balancing plasticity and robustness in binary-fate cellular decision systems. Masters thesis, Indian Institute of Science Education and Research Kolkata.

Text (MS Dissertation of Kushal Haldar (Roll No. 20MS048)) 20MS048_Thesis_file.pdf - Submitted Version Restricted to Repository staff only Download (9MB)

Abstract

Regulatory networks governing choices between two distinct cellular fates are often characterized by ’structural balance’, wherein they are comprised of two mutually inhibitory teams of genes such that interactions within the same team tend to be activating and interactions across teams tend to be inhibiting. Large networks are thus essentially reduced to higher order toggle switches that give rise to bimodal phenotypic landscapes, with each mode corresponding to a phenotype where one team of genes is highly expressed while the other is repressed. Though phenotypes having one team maximally expressed at the expense of the other are the dominant steady states of these networks, there is ample experimental and theoretical evidence for the existence of less frequent intermediate states that contribute to plasticity in phenotypic switching processes such as epithelial-mesenchymal transition. There also tend to be slight deviations from an ideal structurally balanced topology in these networks due to the presence of small numbers of connections whose activating/inhibiting natures contradict the team configuration of the network. This thesis attempts to show how the presence of such contradictory edges is essential for optimizing the plasticity and robustness of the emergent phenotypic landscape. Using a discrete spin-glass model, we find that within a certain limit, the presence of small numbers of ’impure’ edges enhances plasticity by giving rise to additional intermediate states between the two modal phenotypes, without appreciably diminishing the bimodality/robustness of the system. Once the number of ’impure’ connections crosses a certain threshold, robustness depreciates rapidly. We conclude that small deviation from ideal structural balance is an evolutionarily conserved characteristic which balances robustness and plasticity in binary-choice cell-fate landscapes

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