Delayed self-regulation leads to novel states in epigenetic landscapes

TL;DR

This paper investigates how time delays in gene regulatory circuits can induce oscillations between cell states, offering new insights into cell differentiation and pluripotency through a nonlinear dynamical model.

Contribution

It introduces a novel model incorporating time delays in gene regulation, revealing oscillatory behaviors that explain experimental observations in cell reprogramming.

Findings

Time delay induces sustained oscillations between cell states.

Oscillatory states may explain pluripotency induction.

Delay effects are crucial in understanding cell differentiation dynamics.

Abstract

The epigenetic pathway of a cell as it differentiates from a stem cell state to a mature lineage-committed one has been historically understood in terms of Waddington's landscape, consisting of hills and valleys. The smooth top and valley-strewn bottom of the hill represents their undifferentiated and differentiated states respectively. Although mathematical ideas rooted in nonlinear dynamics and bifurcation theory have been used to quantify this picture, the importance of time delays arising from multistep chemical reactions or cellular shape transformations have been ignored so far. We argue that this feature is crucial in understanding cell differentiation and explore the role of time delay in a model of a single gene regulatory circuit. We show that the interplay of time-dependant drive and delay introduces a new regime where the system shows sustained oscillations between the two admissible steady states. We interpret these results in the light of recent perplexing experiments on inducing the pluripotent state in mouse somatic cells. We also comment on how such an oscillatory state can provide a framework for understanding more general feedback circuits in cell development.