A probabilistic Boolean model on hair follicle cell fate regulation by TGF-5

Hair follicles (HFs) are mini skin organs that undergo cyclic growth. Various signals regulate HF cell fate decisions jointly. Recent experimental results suggest that transforming growth factor beta (TGF-5) exhibits a dual role in HF cell fate regu-lation that can be either anti-or pro-apoptosis. To understand the underlying mechanisms of HF cell fate control, we develop a novel probabilistic Boolean network (pBN) model on the HF epithelial cell gene regulation dynamics. First, the model is derived from literature, then refined using single-cell RNA sequencing data. Using the model, we both explore the mechanisms under-lying HF cell fate decisions and make predictions that could potentially guide future experiments: 1) we propose that a threshold -like switch in the TGF-5 strength may necessitate the dual roles of TGF-5 in either activating apoptosis or cell proliferation, in cooperation with bone morphogenetic protein (BMP) and tumor necrosis factor (TNF) and at different stages of a follicle growth cycle; 2) our model shows concordance with the high-activator-low-inhibitor theory of anagen initiation; 3) we predict that TNF may be more effective in catagen initiation than TGF-5, and they may cooperate in a two-step fashion; 4) finally, predictions of gene knockout and overexpression reveal the roles in HF cell fate regulations of each gene. Attractor and motif analysis from the associated Boolean networks reveal the relations between the topological structure of the gene regulation network and the cell fate regulation mechanism. A discrete spatial model equipped with the pBN illustrates how TGF-5 and TNF cooperate in initiating and driving the apoptosis wave during catagen.