Dynamics of cell-type transition mediated by epigenetic modifications

TL;DR

This paper presents a hybrid computational model demonstrating how stochastic inheritance of epigenetic states influences stem cell differentiation, dedifferentiation, and transdifferentiation, providing insights into regenerative medicine.

Contribution

It introduces a comprehensive multi-scale model integrating gene regulation, epigenetics, and cell regeneration to explain cell fate decisions driven by epigenetic inheritance.

Findings

Random inheritance of epigenetic states induces cell differentiation and reprogramming.

Interfering with epigenetic modifications affects cell fate probabilities.

Additional transcription factors influence dedifferentiation and transdifferentiation outcomes.

Abstract

Maintaining tissue homeostasis requires appropriate regulation of stem cell differentiation. The Waddington landscape posits that gene circuits in a cell form a potential landscape of different cell types, wherein cells follow attractors of the probability landscape to develop into distinct cell types. However, how adult stem cells achieve a delicate balance between self-renewal and differentiation remains unclear. We propose that random inheritance of epigenetic states plays a pivotal role in stem cell differentiation and present a hybrid model of stem cell differentiation induced by epigenetic modifications. Our comprehensive model integrates gene regulation networks, epigenetic state inheritance, and cell regeneration, encompassing multi-scale dynamics ranging from transcription regulation to cell population. Through model simulations, we demonstrate that random inheritance of epigenetic states during cell divisions can spontaneously induce cell differentiation, dedifferentiation, and transdifferentiation. Furthermore, we investigate the influences of interfering with epigenetic modifications and introducing additional transcription factors on the probabilities of dedifferentiation and transdifferentiation, revealing the underlying mechanism of cell reprogramming. This \textit{in silico} model provides valuable insights into the intricate mechanism governing stem cell differentiation and cell reprogramming and offers a promising path to enhance the field of regenerative medicine.