An enriched network motif family regulates multistep cell fate transitions with restricted reversibility

Abstract

Multistep cell fate transitions with stepwise changes of transcriptional profiles are common to many developmental, regenerative and pathological processes. The multiple intermediate cell lineage states can serve as differentiation checkpoints or branching points for channeling cells to more than one lineages. However, mechanisms underlying these transitions remain elusive. Here, we explored gene regulatory circuits that can generate multiple intermediate cellular states with stepwise modulations of transcription factors. With unbiased searching in the network topology space, we found a motif family containing a large set of networks can give rise to four attractors with the stepwise regulations of transcription factors, which limit the reversibility of three consecutive steps of the lineage transition. We found that there is an enrichment of these motifs in a transcriptional network controlling the early T cell development, and a mathematical model based on this network recapitulates multistep transitions in the early T cell lineage commitment. By calculating the energy landscape and minimum action paths for the T cell model, we quantified the stochastic dynamics of the critical factors in response to the differentiation signal with fluctuations. These results are in good agreement with experimental observations and they suggest the stable characteristics of the intermediate states in the T cell differentiation. These dynamical features may help to direct the cells to correct lineages during development. Our findings provide general design principles for multistep cell linage transitions and new insights into the early T cell development. The network motifs containing a large family of topologies can be useful for analyzing diverse biological systems with multistep transitions. Author summary The functions of cells are dynamically controlled in many biological processes including development, regeneration and disease progression. Cell fate transition, or the switch of cellular functions, often involves multiple steps. The intermediate stages of the transition provide the biological systems with the opportunities to regulate the transitions in a precise manner. These transitions are controlled by key regulatory genes of which the expression shows stepwise patterns, but how the interactions of these genes can determine the multistep processes were unclear. Here, we present a comprehensive analysis on the design principles of gene circuits that govern multistep cell fate transition. We found a large network family with common structural features that can generate systems with the ability to control three consecutive steps of the transition. We found that this type of networks is enriched in a gene circuit controlling the development of T lymphocyte, a crucial type of immune cells. We performed mathematical modeling using this gene circuit and we recapitulated the stepwise and irreversible loss of stem cell properties of the developing T lymphocytes. Our findings can be useful to analyze a wide range of ge...

A Quantitative Evaluation of Topological Motifs and Their Coupling in Gene Circuit State Distributions

“…This approach usually only considers the frequency of circuit motifs' appearance, but not their functionality, for initial identification. To address this issue, recent studies 5,6,14,15 have been focused on identifying functionally relevant circuit motifs capable of producing specific dynamical behaviors using mathematical modeling . CC-BY-NC-ND 4.0 International license available under a was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”

“…19.500691 doi: bioRxiv preprint and then analyzing them for enriched motifs. These types of approaches have been devised and applied to elucidate circuits capable of generating oscillations 16,17,18 and multiple stable steady states 6,19,20 . Ye et al 6 identified three-node circuits capable of generating stepwise transitions between four states with limited reversibility.…”

“…In this study, we performed the first-ever comprehensive analysis on all non-redundant four-node transcriptional regulatory circuits. Compared to previous studies on three-node circuits 6,14,23 , our analysis has the following advantages. First, there are around sixty thousand non-redundant four-node circuits (see Methods), which is still manageable to perform extensive computational simulations and is sufficiently large for a robust statistical analysis.…”

Potential Landscapes, Bifurcations, and Robustness of Tristable Networks

“…Such situations have recently been shown to occur in the multistep transitions in the early T cell lineage commitment. 50 Broken branches are also known to generate unusual bifurcations, such as Isola bifurcation, that were proposed to be relevant in the long term memory 51 and in the neural stem cell development. 52 The proposed potential based method will not face such problem as it determines the steady states based on the local extremum in the potential landscape.…”

“…However, for more complex networks such dimensional reduction may not always be possible. However, recently Ye et al 50 have investigated network topologies that have the potential to generate irreversible tetrastability with sequential activation of genes, and they found enrichment of certain subnetworks responsible for such behavior in early T cell development. Consistent with our work, the occurrence frequency of MISA motif in these subnetworks, particularly in Type-II, is quite large.…”