Cell-type switches induced by stochastic histone modification inheritance

Rongsheng Huang,Jinzhi Lei

doi:10.3934/dcdsb.2019074

Abstract

Cell plasticity is important for tissue developments during which somatic cells may switch between distinct states. Genetic networks to yield multistability are usually required to yield multiple states, and either external stimuli or noise in gene expressions are trigger signals to induce cell-type switches. In many biological systems, cells show highly plasticity and can switch between different states spontaneously, but maintaining the dynamic equilibrium of the cell population. Here, we considered a mechanism of spontaneous cell-type switches through the combination between gene regulation network and stochastic epigenetic state transitions. We presented a mathematical model that consists of a standard positive feedback loop with changes of histone modifications during cell cycling. Based on the model, nucleosome state of an associated gene is a random process during cell cycling, and hence introduces an inherent noise to gene expression, which can automatically induce cell-type switches in cell cycling. Our model reveals a simple mechanism of spontaneous cell-type switches through a stochastic histone modification inheritance during cell cycle. This mechanism is inherent to the normal cell cycle process, and is independent to the external signals.

Highlights

Cell-type switches are important in mammalian development and the progress of of complex diseases, such as immune responses and drug resistance
We show that the dynamic behavior of histone modification in the cell division can induce spontaneous cell-type switches during normal development process, from which the Waddington landscape is constructed
While we fixed a = 0.5 and varied b, the stationary protein distribution is mostly unchanged with different b values (Fig.7B). These results show that cell plasticity can be explained by the stochastic inheritance of epigenetic states, and the epigenetic state regulation is important for determining the stationary distribution of gene expression in a colony of cell populations

Summary

Introduction

Cell-type switches are important in mammalian development and the progress of of complex diseases, such as immune responses and drug resistance. We assumed that the cell type is represented by the expression of a marker gene; the encoded protein regulates (either directly or indirectly) its own promoter activity to form a positive feedback to maintain the bistable transcriptional landscape. This type of simple motif has been extensively studied in many systems with different states in response to various induction stimulus, variance in the induction stimulus are able to induce switches between the two stable states [1, 16, 22, 25, 41, 47, 64].

Result

Findings

Discussion