Non-genetic heterogeneity, criticality and cell differentiation

Abstract

The different cell types in a living organism acquire their identity through the process of cell differentiation in which multipotent progenitor cells differentiate into distinct cell types. Experimental evidence and analysis of large-scale microarray data establish the key role played by a two-gene motif in cell differentiation in a number of cell systems. The two genes express transcription factors which repress each other's expression and autoactivate their own production. A number of theoretical models have recently been proposed based on the two-gene motif to provide a physical understanding of how cell differentiation occurs. In this paper, we study a simple model of cell differentiation which assumes no cooperativity in the regulation of gene expression by the transcription factors. The latter repress each other's activity directly through DNA binding and indirectly through the formation of heterodimers. We specifically investigate how deterministic processes combined with stochasticity contribute in bringing about cell differentiation. The deterministic dynamics of our model give rise to a supercritical pitchfork bifurcation from an undifferentiated stable steady state to two differentiated stable steady states. The stochastic dynamics of our model are studied using the approaches based on the Langevin equations and the linear noise approximation. The simulation results provide a new physical understanding of recent experimental observations. We further propose experimental measurements of quantities like the variance and the lag-1 autocorrelation function in protein fluctuations as the early signatures of an approaching bifurcation point in the cell differentiation process.

Allee dynamics: Growth, extinction and range expansion

“…Recently, a large number of studies have been carried out on the early signatures of tipping point transitions involving sudden regime shifts in systems as diverse as ecosystems, financial markets, population biology, complex diseases, gene expression dynamics and cell differentiation [15,16,17,18]. The early signatures include the critical slowing down and its associated effects, namely, rising variance and the lag-1 autocorrelation function as the bifurcation point is approached.…”

Criticality in Cell Differentiation

“…There is a large body of literature on generic signatures of approaching bifurcation points in diverse systems [30,31] conferring a universal character on criticality associated with such systems. The search for such signatures in the dynamical behavior of gene networks is in its early stages with only a few theoretical and experimental studies carried out to date [12,18,24,25]. In this context, we mention a recent experimental result [40] which may be interpreted in terms of an approaching critical point.…”

“…The distribution of the (x 1 , x 2 ) values has been obtained by solving the Langevin equations [12]. The variance increases as the bifurcation point is approached.…”

“…Similar studies on the signatures of regime shifts in gene expression dynamics have been carried out in Refs. [12,32]. Regime shifts mostly occur at bifurcation points or may be noise-induced.…”

“…If the transition occurs via a bifurcation, the increasing noise may be attributed to a rising variance associated with criticality. The study of Mojtahedi et al [24] acquires significance for providing experimental support to the criticality conjecture in cell differentiation [12]. The generality of the idea needs to be tested in different cell lines.…”