Pluripotency, differentiation, and reprogramming: A gene expression dynamics model with epigenetic feedback regulation

TL;DR

This paper presents a gene regulatory network model incorporating epigenetic feedback to understand pluripotency, differentiation, and reprogramming, highlighting how gene expression dynamics and epigenetic modifications influence cell state transitions and stability.

Contribution

It introduces a dynamical-systems model that links gene expression with epigenetic feedback, providing insights into cell differentiation and reprogramming mechanisms.

Findings

Cell differentiation begins with oscillatory pluripotent gene expression.

Epigenetic modifications stabilize cell states and create barriers to reprogramming.

Overexpression of specific genes can reprogram differentiated cells to pluripotency.

Abstract

Characterization of pluripotent states, in which cells can both self-renew and differentiate, and the irreversible loss of pluripotency are important research areas in developmental biology. In particular, an understanding of these processes is essential to the reprogramming of cells for biomedical applications, i.e., the experimental recovery of pluripotency in differentiated cells. Based on recent advances in dynamical-systems theory for gene expression, we propose a gene-regulatory-network model consisting of several pluripotent and differentiation genes. Our results show that cellular-state transition to differentiated cell types occurs as the number of cells increases, beginning with the pluripotent state and oscillatory expression of pluripotent genes. Cell-cell signaling mediates the differentiation process with robustness to noise, while epigenetic modifications affecting gene expression dynamics fix the cellular state. These modifications ensure the cellular state to be protected against external perturbation, but they also work as an epigenetic barrier to recovery of pluripotency. We show that overexpression of several genes leads to the reprogramming of cells, consistent with the methods for establishing induced pluripotent stem cells. Our model, which involves the inter-relationship between gene expression dynamics and epigenetic modifications, improves our basic understanding of cell differentiation and reprogramming.