A new mechanism of stem cell differentiation through slow binding/unbinding of regulators to genes

Understanding differentiation, a biological process from a multipotent stem or progenitor state to a mature cell is critically important. We developed a theoretical framework to quantify the underlying potential landscape and pathways for cell development and differentiation. We proposed a new mechanism of differentiation and found the differentiated states can emerge from the slow binding/unbinding of regulatory proteins to gene promoters. With slow promoter binding/unbinding, we found multiple meta-stable differentiated states, which can explain the origin of multiple states observed in recent experiments. The kinetic time for the differentiation and reprogramming strongly depends on the time scale of the promoter binding/unbinding processes. We discovered an optimal speed for differentiation for certain promoter binding/unbinding rates. Future experiments might be able to tell if cells differentiate at that optimal speed. We also quantified irreversible kinetic pathways for the differentiation and reprogramming, which captures the non-equilibrium dynamics in multipotent stem or progenitor cells.