A new mechanism of development and differentiation through slow binding/unbinding of regulatory proteins to the genes

TL;DR

This paper presents a theoretical framework revealing how slow binding and unbinding of regulatory proteins to gene promoters can lead to multiple differentiated states, influencing cell development pathways and their irreversibility.

Contribution

It introduces a novel mechanism for cell differentiation based on slow promoter binding/unbinding, explaining multiple states and irreversibility in cell development.

Findings

Differentiated states emerge from slow promoter binding/unbinding.

Multiple meta-stable states can exist due to slow binding/unbinding.

Differentiation pathways are found to be irreversible.

Abstract

Understanding the differentiation, a biological process from a multipotent stem or progenitor state to a mature cell is critically important. We develop a theoretical framework to quantify the underlying potential landscape and biological paths for cell development and differentiation. We propose a new mechanism of differentiation and development through binding/unbinding of regulatory proteins to the gene promoters. We found indeed the differentiated states can emerge from the slow promoter binding/unbinding processes. Furthermore, under slow promoter binding/unbinding, we found multiple meta-stable differentiated states. This can explain the origin of multiple states observed in the recent experiments. In addition, the kinetic time quantified by mean first passage transition 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 binding/unbinding rates of regulatory proteins to promoters. More experiments in the future might be able to tell if cells differentiate at at that optimal speed. In addition, we quantify kinetic pathways for the differentiation and reprogramming. We found that they are irreversible. This captures the non-equilibrium dynamics in multipotent stem or progenitor cells. Such inherent time-asymmetry as a result of irreversibility of state transition pathways as shown may provide the origin of time arrow for cell development.