Dynamic network biomarker factors orchestrate cell-fate determination at tipping points during hESC differentiation
Lin Li, Yilin Xu, Lili Yan, Xiao Li, Fei Li, Zhuang Liu, Chuanchao Zhang, Yuan Lou, Dong Gao, Xin Cheng, Luonan Chen
Abstract
•M-DNB model identifies two tipping points of hESC differentiation.•Five M-DNB factors are master regulators in hESC differentiation.•Before tipping points, M-DNB factors orchestrate cell fate determination. The generation of ectoderm, mesoderm, and endoderm layers is the most critical biological process during the gastrulation of embryo development. Such a differentiation process in human embryonic stem cells (hESCs) is an inherently nonlinear multi-stage dynamical process which contain multiple tipping points playing crucial roles in the cell-fate decision. However, the tipping points of the process are largely unknown, letting alone the understanding of the molecular regulation on these critical events. Here by designing a module-based dynamic network biomarker (M-DNB) model, we quantitatively pinpointed two tipping points of the differentiation of hESCs toward definitive endoderm, which leads to the identification of M-DNB factors (FOS, HSF1, MYCN, TP53, and MYC) of this process. We demonstrate that before the tipping points, M-DNB factors are able to maintain the cell states and orchestrate cell-fate determination during hESC (ES)-to-ME and ME-to-DE differentiation processes, which not only leads to better understanding of endodermal specification of hESCs but also reveals the power of the M-DNB model to identify critical transition points with their key factors in diverse biological processes, including cell differentiation and transdifferentiation dynamics. The generation of ectoderm, mesoderm, and endoderm layers is the most critical biological process during the gastrulation of embryo development. Such a differentiation process in human embryonic stem cells (hESCs) is an inherently nonlinear multi-stage dynamical process which contain multiple tipping points playing crucial roles in the cell-fate decision. However, the tipping points of the process are largely unknown, letting alone the understanding of the molecular regulation on these critical events. Here by designing a module-based dynamic network biomarker (M-DNB) model, we quantitatively pinpointed two tipping points of the differentiation of hESCs toward definitive endoderm, which leads to the identification of M-DNB factors (FOS, HSF1, MYCN, TP53, and MYC) of this process. We demonstrate that before the tipping points, M-DNB factors are able to maintain the cell states and orchestrate cell-fate determination during hESC (ES)-to-ME and ME-to-DE differentiation processes, which not only leads to better understanding of endodermal specification of hESCs but also reveals the power of the M-DNB model to identify critical transition points with their key factors in diverse biological processes, including cell differentiation and transdifferentiation dynamics.