A multiscale model of epigenetic heterogeneity reveals the kinetic routes of pathological cell fate reprogramming

Abstract

The inherent capacity of somatic cells to switch their phenotypic status in response to damage stimuli in vivo might have a pivotal role in ageing and cancer. However, how the entry-exit mechanisms of phenotype reprogramming are established remains poorly understood. In an attempt to elucidate such mechanisms, we herein introduce a stochastic model of combined epigenetic regulation (ER)-gene regulatory network (GRN) to study the plastic phenotypic behaviours driven by ER heterogeneity. Furthermore, based on the existence of multiple scales, we formulate a method for stochastic model reduction, from which we derive an efficient hybrid simulation scheme that allows us to deal with such complex systems. Our analysis of the coupled system reveals a regime of tristability in which pluripotent stem-like and differentiated steady-states coexist with a third indecisive state. Crucially, ER heterogeneity of differentiation genes is for the most part responsible for conferring abnormal robustness to pluripotent stem-like states. We then formulate epigenetic heterogeneity-based strategies capable of unlocking and facilitating the transit from differentiation-refractory (pluripotent stem-like) to differentiation-primed epistates. The application of the hybrid numerical method validated the likelihood of such switching involving solely kinetic changes in epigenetic factors. Our results suggest that epigenetic heterogeneity regulates the mechanisms and kinetics of phenotypic robustness of cell fate reprogramming. The occurrence of tunable switches capable of modifying the nature of cell fate reprogramming from pathological to physiological might pave the way for new therapeutic strategies to regulate reparative reprogramming in ageing and cancer. Author summaryCertain modifications of the structure and functioning of the protein/DNA complex 1 called chromatin can allow adult, fully differentiated cells to adopt a stem cell-like 2 pluripotent state in a purely epigenetic manner, not involving changes in the underlying 3 DNA sequence. Such reprogramming-like phenomena may constitute an innate 4 reparative route through which human tissues respond to injury and could also serve as 5 a novel regenerative strategy in human pathological situations in which tissue or organ 6 repair is impaired. However, it should be noted that in vivo reprogramming would be 7 capable of maintaining tissue homeostasis provided the acquisition of pluripotency 8 features is strictly transient and accompanied by an accurate replenishment of the 9 specific cell types being lost. Crucially, an excessive reprogramming to pluripotency in 10 the absence of controlled re-differentiation would impair the repair or the replacement of 11 damaged cells, thereby promoting pathological alterations of cell fate. A mechanistic 12 understanding of how the degree of chromatin plasticity dictates the reparative versus 13 pathological behaviour of in vivo reprogramming to rejuvenate aged tissues while 14 preventing tumorigenesis is urgently needed, including especially th...

Bivalent chromatin as a therapeutic target in cancer: Anin silicopredictive approach for combining epigenetic drugs

“…Modified residues enhance recruitment of epigenetic enzymes, providing a positive feedback mechanism where residue modification increases the rate of further me3 addition (see Figure 1(b)). Following previous models of ER [33,34], we account for such positive feedbacks by taking the rate constants associated to each of the me3-addition MM reactions to change linearly with the number of corresponding modified residues (see Table S.1 in S1 File). Furthermore, recruitment of epigenetic enzymes to H3K4 is also enhanced by the presence of transcription factors [41][42][43] (see Figure 1(b)).…”

“…Such transitions are driven by intrinsic or extrinsic fluctuations [29,30]. Noteworthy, the topography of such landscapes depends on a complex set of biochemical interactions and, in particular, on the values of the corresponding set of rate constants [17,[31][32][33][34]. These constants strongly depend on protein structure (e.g.…”

“…Thus, an epigenetic landscape emerges from a particular genotype [17], and therefore can be interpreted as a representation of the genotype-phenotype map [35][36][37][38][39][40]. Beyond their dependence on DNA sequence, in the case of biochemical reactions involving enzymatic catalysis, the associated rate constants depend also on the concentration of metabolic cofactors [33,34], which may differ among cells thus adding a further source of cell-to-cell heterogeneity.…”

“…In order to shed some light on the role of bivalent chromatin as a therapeutic target, we propose a mathematical model of a simple gene regulatory circuit with a bivalent promoter (see Figures 1(a) and (b)). Specifically, our model addresses mutual nonlinear feedbacks between marked nucleosomes and transcription factors (TFs), which drive not only the rates of both addition of new marks and TF synthesis [41][42][43][44][45], but also the heterogeneity of cellular populations [17,33,34,46,47].…”

“…Our analysis of a bivalent TF is based on the explicit calculation of the Waddington landscape for the system under consideration, which allows us to exhaustively classify the set of possible landscape topographies. We account for the effects of heterogeneous behaviour in the epigenetic-regulatory system [46,47] by means of an ensemble approach previously developed [33,34], in which we take advantage of the direct connection between landscape topography and the rate constants that characterise the underlying biochemical networks from which it emerges. After validating our ensemble approach against quantitative experimental data [20,21,65], we finally address the issue of what epigenetic strategies are more effective regarding their ability to overcome heterogeneity.…”