Cell-Type Switches Induced by Stochastic Histone Modification Inheritance

Abstract

Cell plasticity is important for tissue developments during which somatic cells may switch between distinct states. Genetic networks to yield multistable states are usually required to yield multiple states, and either external stimuli or noise in gene expressions are trigger signals to induce cell-type switches between the states. In many biological systems, cells show highly plasticity and can switch between different state 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 with 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.2010 Mathematics Subject Classification. Primary: 92B05, 91B70; Secondary : 92D25. 1 2 RONGSHENG HUANG AND JINZHI LEI changes in the activities of regulators in the gene regulation network is one of the driving force to induce cell type switch, e.g., stem cell differentiation [10,23,24,42]. During development, cells undergo a unidirectional course of differentiation, which can be viewed as a dynamical process on the Waddington epigenetic landscape with multistable states, the input signals can change the landscape to guide the transition between different states [15,19,72].Chromatin regulators play crucial roles in establishing and maintaining gene expression states [4,30]. Histone modifications and DNA methylations are important epigenetic states that can regulate the chromatin state of a DNA sequence, and modulate the gene expression dynamics. These epigenetic modifications are modulated by intercellular enzyme activities, and hence dynamically change over time and during cell cycle [50]. The stochastic epigenetic inheritance during cell cycle can result in spontaneous alteration of epigenetic state during development; epigenetic changes in regulatory loci often correlate with expression changes during stem cell differentiation [3,8,27,58,73].Here, to investigate how stochastic epigenetic inheritance affect the dynamical process of cell fate decision, we studied a computational model that combines positive feedback regulation with histone modification of the gene promoter. Moreover, cell cycle was included in the model through the stochastic inheritance during cell cycle. 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 t...

Emergent dynamics of a three-node regulatory network explain phenotypic switching and heterogeneity: a case study of Th1/Th2/Th17 cell differentiation

“…For instance, the Foxp3 promoter is not epigenetically repressed in Th17 cells, possibly enabling Th17-Treg plasticity (Wei et al ., 2009). In our phenomenological model which does not explicitly capture the molecular details of epigenetic repression (Huang and Lei, 2019; Zhao et al ., 2021), a bivalent chromatin state can be conceptually mapped on to the regions of relatively weak epigenetic influence of one master regulator on others. Thus, the weaker the epigenetic influence of node A on node B (α AB ) relative to that of node B on node A (α BA ), the higher the expected plasticity of the phenotype driven by node A.…”

Mathematical Modeling of Histone Modifications Reveals the Formation Mechanism and Function of Bivalent Chromatin

“…In the present model, we do not take into account the transcription processes, which have been implicated in the formation of bivalent chromatin (Voigt et al, 2013). Recent theoretical analyses have shown that incorporating the feedback from transcriptional products into the histone modification regulation can induce intermediate states (Huang and Lei, 2019;Zhang et al, 2019). So, it will be interesting to investigate the effect of transcription processes on the formation of bivalent chromatin in a model coupling both transcription processes and histone modification regulation.…”

Beyond Deterministic Models in Drug Discovery and Development

“…The second issue refers to the ability for randomness to produce spontaneous transitions, causing a system to switch from one stable state to another. In fact, some models posit that this ability of stochastic systems is fundamental to cell plasticity [ 9 , 10 ] and, hence, it could be an important feature to consider for understanding cancer progression [ 11 , 12 ].…”