Modeling signaling‐dependent pluripotency with Boolean logic to predict cell fate transitions

Abstract

Pluripotent stem cells (PSCs) exist in multiple stable states, each with specific cellular properties and molecular signatures. The mechanisms that maintain pluripotency, or that cause its destabilization to initiate development, are complex and incompletely understood. We have developed a model to predict stabilized PSC gene regulatory network (GRN) states in response to input signals. Our strategy used random asynchronous Boolean simulations (R‐ABS) to simulate single‐cell fate transitions and strongly connected components (SCCs) strategy to represent population heterogeneity. This framework was applied to a reverse‐engineered and curated core GRN for mouse embryonic stem cells (mESCs) and used to simulate cellular responses to combinations of five signaling pathways. Our simulations predicted experimentally verified cell population compositions and input signal combinations controlling specific cell fate transitions. Extending the model to PSC differentiation, we predicted a combination of signaling activators and inhibitors that efficiently and robustly generated a Cdx2+Oct4− cells from naïve mESCs. Overall, this platform provides new strategies to simulate cell fate transitions and the heterogeneity that typically occurs during development and differentiation.

Regulatory network characterization in development: challenges and opportunities

“…This method has been exploited to guide the identification of TFs and cell states 39 . Boolean simulation models randomly pick genes and toggle them asynchronously to predict the cell fate transition and heterogonous cell response, which has been used to recapitulate signal-dependent cell differentiation 40 . Weighted gene co-expression network analysis (WGCNA) was also used to construct the regulatory network, to determine functional key players of embryonic development, and to uncover potential functional modules 41 , 42 .…”

Gene regulatory network (GRN) embedded agents connect cellular decision making to human pluripotent stem cell derived germ layer-like pattern formation

“…Pluripotency-maintaining GRNs in "individual" mouse and human PSCs have been extensively studied by us and others (Yachie-Kinoshita et al, 2018;Dunn et al, 2014;Dunn et al, 2019;Lin et al, 2018;Xu et al, 2014;Okawa and del Sol, 2015;Ng and Surani, 2011;Kalmar et al, 2009). Briefly, core pluripotency factors OCT4, NANOG, and SOX2 are closely linked via autoregulatory interactions (Boyer et al, 2005;Yan et al, 2013).…”

Inference of Genome-Scale Gene Regulatory Networks: Are There Differences in Biological and Clinical Validations?

“…Gene regulatory networks (GRNs) provide a framework for representing condition and disease-specific interactions. For this reason, such networks are playing an increasingly important role in biology and medicine and translational applications derived from these [9][10][11][12][13][14][15][16][17][18]. Despite the importance of gene regulatory networks and their ample application opportunities, there are still many questions that are either unanswered or misunderstood that present serious obstacles to basic and translational research.…”