Serum response factor reduces gene expression noise and confers cell state stability

Abstract: The role of serum response factor (Srf), a central mediator of actin dynamics and mechanical signaling, in cell identity regulation is debated to be either a cell identity stabilizer or destabilizer. We thus investigated the role of Srf in cell fate stability using mouse pluripotent stem cells, one of the very few cell types that can tolerate null Srf. Despite the fact that serum-containing cultures yield heterogeneous gene expression, deletion of Srf in mouse pluripotent stem cells leads to further exacerbated cell state heterogeneity. The exaggerated heterogeneity is not only detectible as increased lineage priming, but also as the 2C-like cell state. Thus, pluripotent cells explore more variety of cellular states in both directions of development surrounding naive pluripotency, a behavior that is constrained by Srf. These results support that Srf functions as a cell state stabilizer, providing rationale for its functional perturbation in cell fate engineering and pathological intervention.